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Over the past century, the field of antibody discovery has undergone significant evolution, excluding the current exploration stage of artificial intelligence‐based antibody generation and the often overlooked non‐animal sourced antibody discovery, which typically requires mature in vitro affinity and the selection of high‐quality antigen formulations. This journey has traversed various stages, from methods involving serum‐based antibody acquisition, the isolation of B cells capable of perpetual antibody production through hybridoma technology, to the in‐depth exploration of genetic material using the phage display system, and the current stage involving diverse single B cell screening techniques. Additionally, the emergence of machine learning has brought impressive scientific and technological breakthroughs across research domains, proving to be a powerful application in the field of antibody discovery. However, each technique comes with its limitations, such as variability and control challenges in serum‐based acquisition, lengthy and difficult hybridoma‐derived antibody development, potential limitations in sequence and epitope diversity due to immunization biases in phage display techniques, and costly single B cell screening. Protein mass spectrometry sequencing, with shorter acquisition time and lower costs, is seen as a shortcut by diagnostic companies, impacting traditional antibody development. In diagnostic antibody development, methodological differences in downstream assays and the impact of constant regions outside the Fv core are often neglected. This paper deeply analyzes challenges, proposing innovative strategies for the next generation of diagnostic antibody development. Aimed at moving closer to the gold standard of antibody discovery, these strategies enhance the competitiveness of diagnostic reagent products. [ABSTRACT FROM AUTHOR]

The article offers update on bone fracture prevention and treatments for conditions such as osteoporosis. It discusses findings of several research including fracture repair via bone remodeling using osteoclasts, potential of high frequency sound waves to convert bone marrow derived mesenchymal stem cells into bone cells, and a demineralised bone paper biomaterial used to advanced the understanding of bone biology, model disease progression and screen drug responses.

This work investigates the existence and asymptotic behavior of solutions to a nonlocal dispersal in‐host viral model with humoral immunity. The model features both spatial movement of virus and humoral immunity response to the virus. This paper gives the principal eigenvalue (H0$\mathcal {H}_0$) of the nonlocal dispersal problem, and it is verified to be a critical value that determines the infection dynamics. The uninfected equilibrium is unique and stable for H0≤0$\mathcal {H}_0\le 0$. For H0>0$\mathcal {H}_0>0$, the equilibrium is not stable, and infected with/without B cells response equilibrium emerges. This paper also establishes the dynamics of infected equilibria. Numerical simulations are carried out to demonstrate the analytical results of this study. [ABSTRACT FROM AUTHOR]

The clonal selection theory (CST) is the centrepiece of the current paradigm used to explain immune recognition and memory. Throughout the past decades, the original CST had been expanded and modified to explain new experimental evidences since its original publication by Burnet. This gave origin to new paradigms that govern experimental immunology nowadays, such as the associative recognition of antigen model and the stranger/danger signal model. However, these new theories also do not fully explain experimental findings such as natural autoimmune immunoglobulins, idiotypic networks, low and high dose tolerance, and dual‐receptor T and B cells. To make sense of these empirical data, some authors have been trying to change the paradigm of immune cognition using a systemic approach, analogies with brain processing and concepts from second‐order cybernetics. In the present paper, we review the CST and some of the theories/hypotheses derived from it, focusing on immune recognition. We point out their main weaknesses and highlight arguments made by their opponents and believers. We conclude that, until now, none of the proposed theories can fully explain the totality of immune phenomena and that a theory of everything is needed in immunology. [ABSTRACT FROM AUTHOR]

Epigallocatechin‐3‐gallate (EGCG) is a major bioactive compound in tea polyphenol extract. After ingestion, EGCG reaches the intestine and may commence anti‐inflammation in the intestinal organ. Thus, in this paper, the anti‐inflammatory effect of EGCG was studied using lipopolysaccharide (LPS)‐induced inflammation in RAW 264.7 cells. LPS induction instigated morphological deformation extensively which was normalized by EGCG. In LPS‐induced macrophage cells, EGCG was found to lower cellular nitric oxide (32% of LPS group) and intercellular ROS level (45.4% of LPS group). It also suppressed the expression of IL‐1β (LPS 132.6 ± 14.6, EGCG 10.67 ± 3.65), IL‐6 (LPS 2994.44 ± 178.5, EGCG 408.33 ± 52.34), TNF‐α (LPS 27.11 ± 2.84, EGCG 1.22 ± 0.03), and iNOS (LPS 40.45 ± 11.17, EGCG 10.24 ± 0.89). The GO function analysis identified that these differential genes involved 24 biological processes, 18 molecular functions, and 19 cellular component‐related processes. KEGG pathway enrichment analysis revealed that LPS significantly affects NF‐κB, TNF, and TLR signaling pathways. Western blotting revealed that EGCG diminished P‐IκB/IκB ratio by 75% and p‐p65/p65 by 50% compared to the LPS group. Finally, Arg‐1 and CD‐206 mRNA expression were determined by RT‐PCR, which was consistent with the RNA‐Seq result. These findings indicate that EGCG exerts an anti‐inflammatory effect by reducing NO and ROS production, suppressing TLR4 protein expression, and inhibiting IκB and p65 phosphorylation. [ABSTRACT FROM AUTHOR]

Allergic rhinitis (AR) is a global health problem with increasing prevalence and association with an enormous medical and socioeconomic burden. New recognition of immune cells such as type 2 innate lymphocytes (ILC2s), T helper (Th2) 2 cells, follicular helper T cells, follicular regulatory T cells, regulatory T cells, B cells, dendritic cells, and epithelial cells in AR pathogenesis has been updated in this review paper. An in‐depth understanding of the mechanisms underlying AR will aid the identification of biomarkers associated with disease and ultimately provide valuable parameters critical to guide personalized targeted therapy. As the only etiological treatment option for AR, allergen‐specific immunotherapy (AIT) has attracted increasing attention, with evidence for effectiveness of AIT recently demonstrated in several randomized controlled trials and long‐term real‐life studies. The exploration of biologics as therapeutic options has only involved anti‐IgE and anti‐type 2 inflammatory agents; however, the cost‐effectiveness of these agents remains to be elucidated precisely. In the midst of the currently on‐going COVID‐19 pandemic, a global life‐threatening disease, although some studies have indicated that AR is not a risk factor for severity and mortality of COVID‐19, this needs to be confirmed in multi‐centre, real‐life studies of AR patients from different parts of the world. [ABSTRACT FROM AUTHOR]

CD38 is a multifunctional receptor and enzyme present on the surface of B lymphocytes, which can induce B lymphocytes proliferation and apoptosis by crosslinking related cytokines to affect the function of B cells, thus affecting immune regulation in humans and promoting tumorigenesis. The level of CD38 expression in B cells has become an important factor in the clinical diagnosis, treatment, and prognosis of malignant tumors and other related diseases. Therefore, studying the relationship between CD38 expression on the surface of B cells and the occurrence of the disease is of great significance for elucidating its association with disease pathogenesis and the clinical targeted therapy. In this paper, we review the effects of CD38 on B‐cell activation, proliferation, and differentiation, and elaborate the functional role and mechanism of CD38 expression on B cells. We also summarize the relationship between the level of CD38 expression on the surface of B cells and the diagnosis, treatment, and prognosis of various diseases, as well as the potential use of targeted CD38 treatment for related diseases. This will provide an important theoretical basis for the scientific research and clinical diagnosis and treatment of B‐cell‐related diseases. [ABSTRACT FROM AUTHOR]

Summary: A subset of individuals with 'primary' or 'idiopathic' immune thrombocytopenia (ITP) who fail to respond to conventional first‐ and second‐line agents or who lose responsiveness are considered to have 'refractory' disease (rITP), placing them at increased risk of bleeding and complications of intensive treatment. However, the criteria used to define the refractory state vary among studies, which complicates research and clinical investigation. Moreover, it is unclear whether rITP is simply 'more severe' ITP, or if there are specific pathogenic pathways that are more likely to result in refractory disease, and whether the presence or development of rITP can be established or anticipated based on these differences. This paper reviews potential biological features that may be associated with rITP, including genetic and epigenetic risk factors, dysregulation of T cells and cytokine networks, antibody affinity and specificity, activation of complement, impaired platelet production and alterations in platelet viability and clearance. These findings indicate the need for longitudinal studies using novel clinically available methodologies to identify and monitor pathogenic T cells, platelet antibodies and other clues to the development of refractory disease. [ABSTRACT FROM AUTHOR]

Summary: Since its first description by Evans in 1951, this syndrome has been linked to chronic immune thrombocytopenia with the concurrent or delayed onset of autoimmune haemolytic anaemia or neutropenia. For decades, the evolution of Evans syndrome (ES) has carried a poor prognosis and often resulted in chronic steroid exposure, multiple immune suppressing medications directed against T or B lymphocytes, and splenectomy. This paper presents a new view of ES based on recent advances in genomics which begin to classify patients based on their underlying molecular variants in previously described primary immune disorders. This has opened up new avenues of targeted therapy or bone marrow transplant at rather than broad long‐term immune suppression or splenectomy. Importantly, recent studies of the full lifespan of ES suggest that at least 80% of those paediatric patients will progress to various clinical or biological immunopathological manifestations with age despite the resolution of their cytopenias. Those patients merit long‐term follow‐up and monitoring in dedicated transition programs to improve outcome at the adult age. [ABSTRACT FROM AUTHOR]

In this issue of I CPT: Pharmacometrics and Systems Pharmacology i , Leonov et al.[1] present a powerful tool for quantitative systems pharmacology (QSP) practitioners and immune modelers: "CYTOCON DB", a comprehensive and manually curated database of publicly available concentrations of cells, cytokines, chemokines, and other molecules in various human organs in both healthy and diseased states. Finally, CYTOCON DB could both generate new databases, and be linked with existing databases for potentially generating both broad and deep knowledge networks in immunology and MID3. [Extracted from the article]

Transgenic mice expressing human major histocompatibility complex class II (MHCII) risk alleles are widely used in autoimmune disease research, but limitations arise due to non‐physiologic expression. To address this, physiologically relevant mouse models are established via knock‐in technology to explore the role of MHCII in diseases like rheumatoid arthritis. The gene sequences encoding the ectodomains are replaced with the human DRB1*04:01 and 04:02 alleles, DRA, and CD74 (invariant chain) in C57BL/6N mice. The collagen type II (Col2a1) gene is modified to mimic human COL2. Importantly, DRB1*04:01 knock‐in mice display physiologic expression of human MHCII also on thymic epithelial cells, in contrast to DRB1*04:01 transgenic mice. Humanization of the invariant chain enhances MHCII expression on thymic epithelial cells, increases mature B cell numbers in spleen, and improves antigen presentation. To validate its functionality, the collagen‐induced arthritis (CIA) model is used, where DRB1*04:01 expression led to a higher susceptibility to arthritis, as compared with mice expressing DRB1*04:02. In addition, the humanized T cell epitope on COL2 allows autoreactive T cell‐mediated arthritis development. In conclusion, the humanized knock‐in mouse faithfully expresses MHCII, confirming the DRB1*04:01 alleles role in rheumatoid arthritis and being also useful for studying MHCII‐associated diseases. [ABSTRACT FROM AUTHOR]

Key clinical message: Ayurveda Rasayana Therapy (ART) may serve as a safe and effective alternative treatment option for chemo‐intolerance high‐grade stage IV follicular lymphoma patients for increasing survival and tumor regression. Follicular lymphoma (FL), also called follicle center lymphoma/nodular lymphoma, observed in the B lymphocytes (B‐cells). Available therapeutic options for follicular lymphoma are associated with various side effects and, patients with co‐morbidities can seldom tolerate the chemotherapy regimens. Rasayana therapy not only resulted in tumor regression and improved survival but also dealt with the adverse effects of previous chemotherapy drugs. Herein, we present a case of a 74‐year‐old female diagnosed with Follicular lymphoma who had undergone three cycles of chemotherapy with unresolved disease outcome and serious adverse events. The patient refused to undergo further cycles of chemotherapy. Her family decided to start Ayurveda treatment for her as an alternative therapy for cancer care. On thorough case taking considering the Ayurveda parameters personalized Rasayana therapy as planned for the patient with an aim for improvement in Quality of Life (QoL), increasing survival, and optimizing body's immune response to fight the tumor. After treatment of 8 months, this case demonstrated partial tumor response as evidenced by PET‐CT‐scan. Quality of Life as evaluated using FACT‐G was also seen improved besides significant improvement in physical performance status evaluated using ECOG. The patient showed a survival of 3.5 years after starting Ayurveda Rasayana Therapy (ART). Rasayana therapy was well tolerated by the patient. This case report indicates the potential role of ART as a therapeutic option in geriatric cancer patients who are not eligible for cytotoxic interventions. Case warrants further systematic investigation to evaluate the potential role of ART in the treatment of geriatric cancer patients. [ABSTRACT FROM AUTHOR]

This study delves into the impact of mesenchymal stem cells derived from bone marrow (BM‐MSCs) and those sourced from dental pulp (DP‐MSCs) on the recovery of motor function and morphological aspects of the rat's sciatic nerve after crush injuries. The findings highlight that the groups treated with BM‐MSCs, DP‐MSCs or a combination of both (BM + DP‐MSCs) displayed enhanced sciatic functional index values when juxtaposed with the sham group. This points to bettered motor functionalities. A deeper morphological analysis showed that all the groups had retained perineurium structure and fascicular arrangement. Notably, the sham and BM‐MSCs groups had very few inconsistencies. All groups showed standard vascular density. Remarkably, the combined treatment group (BM + DP‐MSCs) presented diminished oedema and a lower count of inflammatory cells. Through immunohistochemical methods, the presence of S100 expression was noted in the groups that underwent treatment. In summation, the study suggests that both BM‐MSCs and DP‐MSCs, whether used singly or in combination, can significantly aid in motor function restoration and morphological enhancements. An interesting observation from our research and earlier studies is that stem cells from dental pulp, which are sourced with less discomfort from milk and wisdom teeth, show a heightened propensity to evolve into nerve cells. This is in contrast to the more uncomfortably acquired BM‐MSCs. [ABSTRACT FROM AUTHOR]

Parsaclisib, a potent and selective phosphatidylinositol 3 kinase δ inhibitor, has been investigated for the treatment of B‐cell malignancies and studied in patients with autoimmune diseases and myelofibrosis. The CITADEL‐101 study (NCT02018861) assessed safety, tolerability, and preliminary efficacy of parsaclisib in patients with relapsed or refractory non‐Hodgkin lymphoma. This study evaluated the cardiac safety of parsaclisib as monotherapy based on data from 72 patients enrolled in the CITADEL‐101 study. Time‐matched pharmacokinetic and ECG measurements were collected at specified times for 69 patients receiving monotherapy in doses of 5, 10, 15, 20, 30, and 45 mg once daily. Based on the categorical outlier analysis, no dose‐dependent effect was observed on the incidence of outliers in QT interval corrected for heart rate (HR) by Fridericia's method (QTcF), HR, or cardiac conduction. Based on central tendency analysis, the least square means (LSMs) (90% confidence interval [CI]) of ΔQTcF from the central tendency analysis ranged from −6.83 (−18.8 to 5.19) to 4.75 ms (0.410–9.09) across dose groups (below 20 ms, the threshold of large QT effects) and was not considered dose dependent. Moreover, the LSMs of ΔHR, ΔPR interval, and ΔQRS interval were minor. From the concentration‐ΔQTcF analyses, the predicted ΔQTcF (90% CI) for all dose levels was between 0.365 (−1.75 to 2.48) and 7.87 ms (0.921–14.8), with the highest upper limit of CIs well below 20 ms, and therefore, a large QT/QTc effect was ruled out up to the highest dose level (45 mg) investigated. Overall, parsaclisib at the dose ranges studied did not reveal concentration‐dependent effects on change in QTcF and did not have a significant effect on HR or cardiac conduction. [ABSTRACT FROM AUTHOR]

Researchers have identified a new monogenic form of systemic lupus erythematosus caused by mutations that result in increased Toll-like receptor 7 (TLR7) signaling. This provides further evidence for the critical role of dysregulated Toll-like receptor 7 (TLR7) signaling in inappropriate activation of self-reactive B cells and autoantibody production. To determine whether mutations in I TLR7 i were able to drive autoantibody production, Brown I et al i .2 generated a mouse model of the Y264H mutation found in the initial patient. [Extracted from the article]

Many of the reviews include discussion of diffusible molecules involved in cell-cell communication during the evolution of innate and adaptive responses (eg, interferons) and how these mediators influence the outcome of the dynamic processes visualized by optical methods. New data on tissue-resident T cells also fall in this category, as do recent observations of perivascular co-localization of effector lymphocytes and presenting cells at sites of effector function within tissues. Technologies are now emerging that will permit combining the protein and cell-based optical imaging methods used to date with recent advances in nucleic acid/genomic methods, especially single-cell sequencing. [Extracted from the article]

This ethnic sensitivity analysis used data from the phase III POLARIX study (NCT03274492) to assess polatuzumab vedotin pharmacokinetics (PKs) in Asian versus non‐Asian patients with previously untreated diffuse large B‐cell lymphoma and examined the appropriateness of extrapolating global study findings to Asian patients. PK and population PK (PopPK) analyses assessed polatuzumab vedotin analyte exposures by ethnicity (Asian [n = 84] vs. non‐Asian [n = 345] patients) and region (patients enrolled from Asia [n = 80] vs. outside Asia [n = 349]). In patients from Asia versus outside Asia, observed mean antibody‐conjugated monomethyl auristatin E (acMMAE) concentrations were comparable (1.2% lower at cycle [C]1 postdose, 4.4% higher at C4 predose; and 6.8% lower at C4 postdose in patients from Asia). Observed mean unconjugated MMAE was lower in patients from Asia by 6.5% (C1 postdose), 20.0% (C4 predose), and 15.3% (C4 postdose). In the PopPK analysis, C6 area under the curve and peak plasma concentrations were also comparable for acMMAE (6.3% and 3.0% lower in Asian vs. non‐Asian patients, respectively) and lower for unconjugated MMAE by 19.1% and 16.7%, respectively. By region, C6 mean acMMAE concentrations were similar, and C6 mean unconjugated MMAE concentrations were lower, in patients enrolled from Asia versus outside Asia, by 3.9%–7.0% and 17.3%–19.7%, respectively. In conclusion, polatuzumab vedotin PKs were similar between Asian and non‐Asian patients by ethnicity and region, suggesting PKs are not sensitive to Asian ethnicity and dose adjustments are not required in Asian patients to maintain efficacy and safety. [ABSTRACT FROM AUTHOR]

Introduction: Dermatomyositis (DM) is often associated with interstitial lung disease (ILD) or pulmonary hypertension (PH). The aim of this study was to investigate the clinical characteristics of DM patients with ILD or PH. Methods: This study retrospectively analysed the clinical characteristics of 372 patients with DM, including cytokines, lymphocyte subsets, immunoglobulin and complement. The DM patients were divided into different groups according to whether complicated with ILD, PH or anti‐melanoma differentiation‐associated gene 5 antibodies (MDA5). A qualitative and quantitative data analysis was performed. Results: IgG, IgA and IgM in the DM‐associated ILD (ILD‐DM) were higher than that of the DM non‐complicating ILD (Non‐ILD‐DM) (p = 0.022, 0.002 and 0.029, respectively). Meanwhile, IL‐6 (p = 0.008) and IL‐10 (p = 0.001) were increased in the DM‐associated PH (PH‐DM) than in the DM non‐complicating PH (Non‐PH‐DM), while IL‐17 (p = 0.004), double positive (DP) cell ratio and B lymphocyte ratio were reduced in the PH‐DM. Moreover, the incidence of ILD and levels of C4 were higher in the DM with MDA5 (MDA5+ DM) than that of the DM without MDA5. Conclusion: ILD‐DM has higher IgG, IgA and IgM than that of Non‐ILD‐DM. PH‐DM has higher IL‐6, IL‐10 and lower IL‐17, DP cell ratio and B lymphocyte ratio than that of Non‐PH‐DM. [ABSTRACT FROM AUTHOR]

To increase the imaging resolution and detection capability, the field strength of static magnetic fields (SMFs) in magnetic resonance imaging (MRI) has significantly increased in the past few decades. However, research on the side effects of high magnetic field is still very inadequate and the effects of SMF above 1 T (Tesla) on B cells have never been reported. Here, we show that 33.0 T ultra‐high SMF exposure causes immunosuppression and disrupts B cell differentiation and signaling. 33.0 T SMF treatment resulted in disturbance of B cell peripheral differentiation and antibody secretion and reduced the expression of IgM on B cell membrane, and these might be intensity dependent. In addition, mice exposed to 33.0 T SMF showed inhibition on early activation of B cells, including B cell spreading, B cell receptor clustering and signalosome recruitment, and depression of both positive and negative molecules in the proximal BCR signaling, as well as impaired actin reorganization. Sequencing and gene enrichment analysis showed that SMF stimulation also affects splenic B cells' transcriptome and metabolic pathways. Therefore, in the clinical application of MRI, we should consider the influence of SMF on the immune system and choose the optimal intensity for treatment. [ABSTRACT FROM AUTHOR]

The contribution of different immune cell subsets, especially T cells, in anti‐tumor immune response is well established. In contrast to T cells, the anti‐tumor contribution of B cells has been scarcely investigated. B‐cells are often overlooked, even though they are important players in a fully integrated immune response and constitute a substantial fraction of tumor draining lymph nodes (TDLNs) known also as Sentinel Nodes. In this project, samples including TDLNs, non‐TDLNs (nTDLNs) and metastatic lymph nodes from 21 patients with oral squamous cell carcinoma were analyzed by flow cytometry. TDLNs were characterized by a significantly higher proportion of B cells compared with nTDLNs (P =.0127). TDLNs‐associated B cells contained high percentages of naïve B cells, in contrary to nTDLNs which contained significantly higher percentages of memory B cells. Patients having metastases in TDLNs showed a significantly higher presence of immunosuppressive B regulatory cells compared with metastasis‐free patients (P =.0008). Elevated levels of regulatory B cells in TDLNs were associated with the advancement of the disease. B cells in TDLNs were characterized by significantly higher expression of an immunosuppressive cytokine—IL‐10 compared with nTDLNs (P =.0077). Our data indicate that B cells in human TDLNs differ from B cells in nTDLNs and exhibit more naïve and immunosuppressive phenotypes. We identified a high accumulation of regulatory B cells within TDLNs which may be a potential obstacle in achieving response to novel cancer immunotherapies (ICIs) in head and neck cancer. [ABSTRACT FROM AUTHOR]

Summary: Undetectable measurable residual disease (MRD) is associated with favourable clinical outcomes in chronic lymphocytic leukaemia (CLL). While assessment is commonly performed using multiparameter flow cytometry (MFC), this approach is associated with limitations including user bias and expertise that may not be widely available. Implementation of unsupervised clustering algorithms in the laboratory can address these limitations and have not been previously reported in a systematic quantitative manner. We developed a computational pipeline to assess CLL MRD using FlowSOM. In the training step, a self‐organising map was generated with nodes representing the full breadth of normal immature and mature B cells along with disease immunophenotypes. This map was used to detect MRD in multiple validation cohorts containing a total of 456 samples. This included an evaluation of atypical CLL cases and samples collected from two different laboratories. Computational MRD showed high correlation with expert analysis (Pearson's r > 0.99 for typical CLL). Binary classification of typical CLL samples as either MRD positive or negative demonstrated high concordance (>98%). Interestingly, computational MRD detected disease in a small number of atypical CLL cases in which MRD was not detected by expert analysis. These results demonstrate the feasibility and value of automated MFC analysis in a diagnostic laboratory. [ABSTRACT FROM AUTHOR]

Rozibafusp alfa (AMG 570) is a first‐in‐class bispecific IgG2‐peptide fusion designed to inhibit inducible T‐cell costimulator ligand (ICOSL) and B‐cell activating factor (BAFF). The pharmacokinetics (PK) and pharmacodynamics (PD) of rozibafusp alfa were investigated in two randomized, placebo‐controlled clinical studies: a phase Ia single ascending‐dose study (7–700 mg subcutaneously (s.c.)) in healthy subjects and a phase Ib multiple ascending‐dose study (70–420 mg s.c. every 2 weeks (q2w)) in patients with rheumatoid arthritis. Rozibafusp alfa exhibited nonlinear PK and dose‐related and reversible dual‐target engagement. Maximal reduction of naïve B cells from baseline (> 40%), reflective of BAFF inhibition, was achieved with rozibafusp alfa exposure (area under the concentration‐time curve from time 0 to time infinity (AUCinf) and AUC within a dosing interval from day 0 to day 14 (AUCtau)) above 51 and 57 days•μg/mL for the single‐dose (≥ 70 mg) and multiple‐dose studies (≥ 70 mg q2w), respectively. ICOSL receptor occupancy on circulating B cells, a surrogate PD end point for ICOSL inhibition, was directly related to drug concentration. PK/PD analysis showed > 90% RO at rozibafusp alfa ≥ 22.2 μg/mL (≥ 420‐mg single dose or ≥ 210 mg q2w multiple dose), with saturation occurring at higher drug concentrations. These results informed the design and dose selection of a phase IIb study assessing the safety and efficacy of rozibafusp alfa in patients with active systemic lupus erythematosus. [ABSTRACT FROM AUTHOR]

Most of the vaccines that are effective against SARS‐CoV‐2 have used the following functional strategies: inactivated viruses, live attenuated viruses, viral vector‐based vaccines, subunit vaccines, recombinant proteins, and DNA/RNA vaccines. Among the vaccines that stimulate the host's immune system with the help of DNA are: undergoing Phase 2/3 trials including INO‐4800 (International Vaccine Institute; Inovio Pharmaceuticals), Symvivo, Canada‐COVID19 (AnGes, Inc.); GX‐19 (Genexine, Inc.). BNT162b2 and mRNA‐1273 vaccines were made by BioNTech/Pfizer/Fosun Pharma group and Moderna/NIAID group, respectively, which are considered as types of RNA vaccines. Vaccines that are based on the viral vector are AstraZeneca, Sputonium, and Johnson‐Jensen. Among the inactive viral vaccines, the following can be mentioned: CoronaVac (Sinovac) WIBP vaccine (Wuhan Institute of Biological Products, Sinopharm), BBIBPCorV (Beijing Institute of Biological Products, Sinopharm), BBV152/Covaxin (Bharat Biotech, ICMR, National Institute of Virology) And among the protein‐based/subunit vaccines, the following can be counted: NVX‐CoV2373: (Novavax); SCB‐2019 vaccine (Clover Biopharmaceuticals AUS Pty Ltd.); Covax‐19 (GeneCure Biotechnologies; Vaxine Pty Ltd.) mRNA vaccines, viral vector vaccines, and protein subunit vaccines cannot cause disease because these vaccines stimulate the immune system to produce antibodies against virus proteins instead of the virus itself (or its antigen). MRNA vaccines increase SARS‐CoV‐2 proteins and ultimately stimulate the production of T and B lymphocytes. The epidemic of HCoVs and their destructive and harmful effects on life has caused the scientific community to seek the production of an effective and efficient vaccine before its catastrophic release. We all need to know that none of us will be healed until the other is healed. The purpose of this review article is to present a selection of existing knowledge in the field of fighting and preventing the coronavirus. [ABSTRACT FROM AUTHOR]

Background: Cutaneous B‐cell lymphoma (CBCL) is part of dermatopathological routine diagnostics. However, in contrast to cutaneous T‐cell lymphomas, there are only a few studies on the prevalence and possible clinical impact of lymphatic vessel involvement. Therefore, this pilot study aimed to quantify the prevalence of lymphovascular involvement in CBCL and to assess the association between lymphovascular involvement and recurrence. Methods: Thirty‐nine patients from two tertiary care hospitals diagnosed with CBCL were retrospectively identified and their biopsies were histopathologically examined for the presence of lymphatic vessel involvement using H&E stain, and CD20 and D2‐40 immunohistochemistry. Clinical data were retrieved from our digital documentation files. Results: Thirty patients were included in the evaluation (nPCFCL = 15, nPCMZL = 10, and nPCLBCL = 5). Lymphovascular involvement occurred in all three types of lymphoma and was present in 14/30 specimens. The presence of lymphatic involvement did not show a significant impact on recurrence rate (p = 0.150). Conclusions: This immunohistochemical pilot study shows that lymphovascular involvement is a relatively frequent finding in primary CBCL. Although no definitive conclusion can be drawn from our findings because of the small sample size, there were no strong signs of tendencies for recurrence in either group. Future studies with larger sample size are warranted to assess the possible clinical implications. [ABSTRACT FROM AUTHOR]

Hypoxia‐inducible factor‐1, a heterodimer of alpha (HIF‐1α) and beta (HIF‐1β or ARNT) subunits, is a major regulator of the transcriptional response to hypoxia. However, HIF‐1α, the oxygen‐regulated subunit, also exerts nontranscriptional functions through interaction with proteins other than ARNT. We have previously shown that the subcellular localization and protein interactions of HIF‐1α are controlled by ERK‐mediated phosphorylation at Ser641/643. When HIF‐1α is modified at these sites, it is nuclear, binds to ARNT, interacts with nucleophosmin 1 (NPM1) and activates transcription of hypoxia‐target genes. On the contrary, unmodified HIF‐1α is bound by chromosomal region maintenance 1 (CRM1), exits the nucleus and, via its association with mortalin, is targeted to the mitochondria to form an antiapoptotic complex. To further characterize the latter function, recombinant fragments of HIF‐1α and mortalin were used for in vitro binding assays and immunoprecipitation experiments to map the respective binding sites and show that their interaction is direct and functional. We could also show that embelin, a natural product and known inhibitor of the mortalin‐p53 interaction, also disrupts the mortalin‐HIF‐1α association and, furthermore, removes unmodified HIF‐1α from mitochondria. Mitochondrial dissociation of HIF‐1α, either by embelin or overexpression of a HIF‐1α peptide harbouring the mortalin binding site, under stress conditions leads to mitochondrial localization of the pro‐apoptotic protein B‐cell lymphoma 2‐associated X protein (Bax) and induction of apoptosis. We suggest that when ERK activity is low under hypoxia, binding of HIF‐1α to mortalin inhibits mitochondrial recruitment of Bax and protects cells from apoptotic cell death. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that often involves abnormal activation of regulatory IFN genes and regulation of B cells by CD4+ T cells. Radical S‐adenosyl methionine domain containing 2 (RSAD2) is a viral suppressor protein regulated by type I IFN, and it has been proven to play an important regulatory role in SLE. However, the mechanism by which RSAD2 participates in the pathogenesis of SLE is unclear. In this study, we observed higher expression levels of RSAD2 in CD4+ T‐cell subsets from the peripheral blood of SLE patients than in those from healthy controls by bioinformatics analysis and validation experiments. We analyzed the expression of RSAD2 in CD4+ T cells of patients with SLE and other autoimmune diseases. In addition, we found that the expression of RSAD2 in CD4+ T cells might be regulated by IFN‐α, and RSAD2 significantly affected the differentiation of Th17 cells and T follicular helper (Tfh) cells. Our findings underlined that RSAD2 may promote B‐cell activation by promoting the differentiation of Th17 and Tfh cells in SLE patients, a process that is regulated by IFN‐α. [ABSTRACT FROM AUTHOR]

The CDC crossmatch test is being phased out in solid organ donor allocation, and standard luminex single antigen bead assays do not differentiate complement activating function of HLA antibodies. The current study investigated the LIFECODES C3d‐binding assay to determine if it could accurately predict actual T and B cell CDC results in a cohort of highly sensitised patients. Nineteen serum samples from different highly sensitised solid organ patients were crossmatched against cells from 62 unique donors, with 174 total T and B cell crossmatches performed. The sera also underwent SAB assay using OLI and LC platforms, and C3d‐binding assay. Complement activating ability of each unique HLA antibody specificity detected using SAB was assigned based on the actual CDC results, which was then used to determine the accuracy of the C3d‐binding assay. The C3d‐binding assay was found to be highly accurate, with sensitivity of 95%, specificity 89% and negative predictive value 97% for class I DSA and the T cell CDC crossmatch results. Furthermore, we found 100% accuracy for prediction of the complement activating function of HLA‐C antibodies. Negative predictive value of above 90% was also found for HLA class II DSA. C3d‐binding proved more accurate than virtual crossmatch alone to predict CDC results. This study confirms that the C3d‐binding assay predicts actual CDC crossmatch results accurately. In particular, the high negative predictive value of the C3d‐binding assay may be extremely useful to define HLA antibodies that do not activate complement in highly sensitised recipients. [ABSTRACT FROM AUTHOR]

The worldwide rollout of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccinations in the last 2 years has produced a multitude of studies investigating T‐cell responses in the peripheral blood and a limited number in secondary lymphoid tissues. As a key component to an effective immune response, vaccine‐specific T follicular helper (Tfh) cells are localized in the draining lymph node (LN) and assist in the selection of highly specific B‐cell clones for the production of neutralizing antibodies. While these cells have been noted in the blood as circulating Tfh (cTfh) cells, they are not often taken into consideration when examining effective CD4+ T‐cell responses, particularly in immunocompromised groups. Furthermore, site‐specific analyses in locations such as the LN have recently become an attractive area of investigation. This is mainly a result of improved sampling methods via ultrasound‐guided fine‐needle biopsy (FNB)/fine‐needle aspiration (FNA), which are less invasive than LN excision and able to be performed longitudinally. While these studies have been undertaken in healthy individuals, data from immunocompromised groups are lacking. This review will focus on both Tfh and cTfh responses after SARS‐CoV‐2 vaccination in healthy and immunocompromised individuals. This area of investigation could identify key characteristics of a successful LN response required for the prevention of infection and viral clearance. This furthermore may highlight responses that could be fine‐tuned to improve vaccine efficacy within immunocompromised groups that are at a risk of more severe disease. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is an autoimmune disease causing significant morbidity and mortality, despite important improvements in its management in the last decades. The objective of this work is to investigate the role of IFN‐γ in the pathogenesis of childhood‐onset systemic lupus erythematosus (cSLE), evaluating the crosstalk between IFN‐α and IFN‐γ and the expression of T‐bet, a transcription factor induced by IFN‐γ, in B cells of patients with cSLE. Expression levels of both IFN‐α and IFN‐γ‐induced genes were upregulated in patients with cSLE. We found increased serum levels of CXCL9 and CXCL10 in patients with cSLE. Type I IFN score decreased with initiation of immunosuppressive treatment; conversely, type II IFN score and levels of CXCL9 were not significantly affected by immunosuppressive treatment. Type II IFN score and CXCL9 were significantly higher in patients with lupus nephritis. We observed the expansion of a population of naïve B cells expressing T‐bet in a cluster of patients with cSLE. IFN‐γ, but not IFN‐α, induced the expression of T‐bet in B cells. Our data suggest that IFN‐γ is hyperactive in cSLE, especially in patients with lupus nephritis, and it is not modulated by therapy. Our data reinforce the potential of IFN‐γ as a therapeutic target in SLE. [ABSTRACT FROM AUTHOR]

In previous studies, Mott cells, an unusual form of plasma cells containing Ig‐inclusion bodies, were frequently observed in peripheral lymphoid tissues in our IgM Fc receptor (FcμR)‐deficient (KO) mouse strain. Because of discrepancies in the reported phenotypes of different Fcmr KO mouse strains, we here examined two additional available mutant strains and confirmed that such enhanced Mott‐cell formation was a general phenomenon associated with FcμR deficiency. Splenic B cells from Fcmr KO mice clearly generated more Mott cells than those from WT mice when stimulated in vitro with LPS alone or a B‐1, but not B‐2, activation cocktail. Nucleotide sequence analysis of the Ig variable regions of a single IgMλ+ Mott‐hybridoma clone developed from splenic B‐1 B cells of Fcmr KO mice revealed the near (VH) or complete (Vλ) identity with the corresponding germline gene segments and the addition of six or five nucleotides at the VH/DH and DH/JH junctions, respectively. Transduction of an FcμR cDNA into the Mott hybridoma significantly reduced cells containing IgM‐inclusion bodies with a concomitant increase in IgM secretion, leading to secreted IgM binding to FcμR expressed on Mott transductants. These findings suggest a regulatory role of FcμR in the formation of Mott cells and IgM‐inclusion bodies. [ABSTRACT FROM AUTHOR]

Naïve B cells become activated and differentiate into antibody‐secreting plasma cells (PCs) when encountering antigens. Here, we reveal that the WW domain‐containing adapter protein with coiled‐coil (Wac), which is important for histone H2B ubiquitination (ubH2B), is essential for PC differentiation. We demonstrate that B cell‐specific Wac knockout mice have severely compromised T cell‐dependent and ‐independent antibody responses. PC differentiation is drastically compromised despite undisturbed germinal center B cell response in the mutant mice. We also observe a significant reduction in global ubH2B in Wac‐deficient B cells, which is correlated with downregulated expression of some genes critical for cell metabolism. Thus, our findings demonstrate an essential role of Wac‐mediated ubH2B in PC differentiation and shed light on the epigenetic mechanisms underlying this process. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell (HSC) transplantation's success lies in its ability to induce immune reconstitution. To date, there is no review published to compare the immune reconstitution among the three sources of HSC: umbilical cord blood (UCB), bone marrow (BM), and peripheral blood (PB). The review aims to analyze the kinetic of immune reconstitution among UCB, PB, and BM in HSC transplant patients by focusing on natural killer (NK) cells, B and T lymphocytes, and neutrophils. A systematic review was conducted through five databases, searching for clinical trials and randomized control trials (RCTs) which analyze the kinetics of immune reconstitution in at least two sources. Selected studies were assessed with Cochrane RoB 2.0. This review included 14 studies, with a total of 2539 subjects. The PB group achieved the fastest time to neutrophil recovery, while the B‐cell count was the highest in the UCB group. The T‐cell count is the lowest in the BM group, and the NK‐cell count does not differ significantly among the three HSC sources. Among the three sources of HSC, there is no superior HSC source for any immune reconstitution parameter. More studies must be conducted to compare the immune reconstitution and clinical outcomes of all HSC sources in specific diseases. [ABSTRACT FROM AUTHOR]

Summary: CD30 is a transmembrane protein from the tumour necrosis factor receptor superfamily. It is expressed on a small subset of activated T and B lymphocytes, and various lymphoid neoplasms. CD30 is a particularly interesting treatment target because its levels are high in tumours but low in healthy tissues. Several therapeutic strategies targeting CD30 have been developed, including monoclonal antibodies, conjugated antibodies (combination of brentuximab vedotin with chemotherapy or immunotherapy), bispecific antibodies and cell and gene therapies, such as anti‐CD30 CAR‐T cells in particular. We briefly review the biology of CD30 which makes it a good therapeutic target, and we describe all of the anti‐CD30 therapies that have emerged to date. [ABSTRACT FROM AUTHOR]

Summary: B‐cell content in the tumour microenvironment (TME) of classic Hodgkin lymphoma (HL) is known to be associated with prognosis. Here we demonstrate that whole slide image analysis using routinely available slides predicts outcomes in patients treated with ABVD in a prospective trial with a high B‐cell content being associated with a favourable prognosis. B cells in the TME did not correlate with B cells in peripheral blood. In the TME maturation, stages of B cells (naive and memory) were consistent. However, we detected down‐regulation of CD73 in HL with low B cells suggestive of an antibody‐independent function of B cells in the TME of HL. [ABSTRACT FROM AUTHOR]

Interleukin 2 receptor (IL‐2R) is released from activated T cell lymphocytes and related to proliferation of B cells and T cells. Beta‐2‐microglobulin (B2M) is synthesized from all nucleated cells and constitutes a major histocompatibility complex class I antigen. In human medicine, high concentrations of these two factors have been found to be related to prognosis in aggressive non‐Hodgkin's lymphoma. In this pilot study, we aimed to assess the correlation between the serum concentration of IL‐2R and B2M and the diagnosis and prognosis of canine lymphoma. This study included 8 healthy dogs and 17 dogs with lymphoma. To measure the serum concentration of IL‐2R and B2M, a commercial enzyme‐linked immunosorbent assay was used. In dogs with lymphoma, IL‐2R concentrations were significantly high at the time of diagnosis, but B2M concentrations were not. In relapsed dogs, both IL‐2R and B2M concentrations were significantly higher than those in the control and chemotherapy response groups. When the serum concentrations of IL‐2R and B2M during chemotherapy were monitored in four relapsed dogs, B2M levels were more closely related with relapse. This study demonstrated that serum IL‐2R and B2M concentration can be a diagnostic or prognostic tool for canine lymphoma. Monitoring of serum B2M concentration seems to be useful for predicting relapse. [ABSTRACT FROM AUTHOR]

Diffuse large B‐cell lymphoma (DLBCL) is frequently treated with chemotherapy incorporating cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP), which induces remission in 80% to 95% of cases. However, not all dogs derive meaningful benefit from CHOP, and prognostic factors for dogs with DLBCL are poorly defined. Serum thymidine kinase 1 (TK1) activity, a marker of tumour cell proliferation, has shown promising initial results as a prognostic biomarker in dogs with multicentric lymphomas. The purpose of this study was to determine if baseline serum TK1 activity is associated with clinical outcome in dogs with CHOP‐treated DLBCL. Baseline serum TK1 activity was measured in banked sera from 98 dogs with CHOP‐treated DLBCL using a commercially available ELISA kit. Data on other potential prognostic factors were abstracted retrospectively from electronic medical records. Multivariable statistical methods were used to identify associations between TK1 and other potential prognostic factors with progression‐free survival (PFS) and attainment of complete remission. TK1 activity at baseline was not associated with PFS (p =.299) or attainment of complete remission (p =.910) following CHOP chemotherapy. Of the other prognostic factors analysed, only purebred (vs. mixed breed) status (HR 8.81, 95% CI 1.68–46.30, p =.010), attainment of complete (vs. partial) remission (HR 0.09, 95% CI 0.02–0.49, p =.006), and baseline serum C‐reactive protein concentration (HR 1.19, 95% CI 1.07–1.32, p =.001) were independently associated with PFS. Based on these findings, baseline serum TK1 activity does not appear to be a useful prognostic biomarker in dogs with CHOP‐treated DLBCL. [ABSTRACT FROM AUTHOR]

Complement‐dependent lymphocytotoxicity cross match (CDC‐XM) is the ultimate test of donor/recipient compatibility prior to organ transplantation. This test is based on cell viability, evaluated under fluorescence microscopy by an operator after proper staining. The determination of the positivity threshold may vary depending on the operator. We developed a new method in which the final step of determining cell viability is automated using the NC‐3000™ (Chemometec®), an image cytometer able to precisely determine the percentage of dead/live cells in a suspension. After T and B donor cells isolation by negative selection, complement‐dependent lysis was performed in macrovolumes in a PCR plate. Then, cell viability was measured by the NC‐3000™. The sensitivity and routine CDC‐XM results of this new method were compared to those of CDC‐XM reference method using Terasaki plates. The sensitivity of CDC‐XM expressed in the ASHI scoring system of this method was similar to the reference method results for a dilution range of the positive controls. Similarly, the results of the new method were comparable in a clinical situation to those obtained with the reference method after a study of 10 cross‐matches, of which 5 cross‐matches with DSA were positive and five cross‐matches without DSA were negative. Moreover, ASHI scores were similar to those obtained using the reference method, and the mortality percentage was reproducible (CV < 15%). The assessment of cell viability by the NC‐3000™ is easy to perform and highly reproducible but requires CDC‐XM to be performed by the macrovolume method. The determination of a precise percentage of viability/mortality by the automation excludes operator variability and allows a better understanding of results close to the decision threshold. [ABSTRACT FROM AUTHOR]

Taurine (Tau) is a special sulphur‐containing amino acid and has been widely used as a dietary supplement. Although Tau exists in lymphocytes in large quantities, the physiological significance of Tau to modulate human immunity is unknown. In the present study, we first found that Tau regulates the B‐cell receptor (BCR)‐mediated signal transduction and induces the B cells activation. The IgG production of mice after ovalbumin immunization was also increased by Tau administration. Moreover, the isothermal titration calorimetry and surface plasmon resonance analysis have shown that Tau specifically bound to the IgG2a‐BCR. The Tau could bind to IgG F(ab′)2 regions via fluorescence spectroscopy analysis. In the molecular docking analysis, Tau bound to the framework regions (FRs) of variable region of the heavy chains (VH) and in the light chains (VL) of IgG2a‐BCR. Our results suggested that Tau could improve the activation of B cells by interaction with the VH/VL FRs of BCR. [ABSTRACT FROM AUTHOR]

We demonstrate that CD193, the eotaxin receptor, is highly expressed on circulating B cells in paediatric schistosomiasis mansoni. CD193 plays a role in directing granulocytes into sites of allergic‐like inflammation in the mucosa, but little is known about its functional significance on human B cells. We sought to characterize CD193 expression and its relationship with S. mansoni infection. We found that CD193+ B cells increased with the intensity of schistosome infection. In addition, a significant negative association was observed between CD193 expression by B cells and IgE production. Decreased IgE levels are generally associated with susceptibility to re‐infection. B cell stimulation with eotaxin‐1 increased CD193 levels whereas IL‐4 led to a reduction. This was supported by plasma levels of eotaxin‐1 correlating with CD193 levels on B cells and other cells. In contrast, CD193 expression was induced on naive B cells with a combination of IL‐10 and schistosome antigens. Whereas T cells had a modest increase in CD193 expression, only B cell CD193 appeared functionally chemotactic to eotaxin‐1. Thus, CD193+ B cells, which co‐express CXCR5, may be enroute to sites with allergic‐like inflammation, such as gastrointestinal follicles, or even to Th2 granulomas, which develop around parasite eggs. Overall, our results suggest that schistosome infection may promote CD193 expression and suppress IgE via IL‐10 and other undefined mechanisms related to B cell trafficking. This study adds to our understanding of why young children may have poor immunity. Nonetheless, praziquantel treatment was shown to reduce percentages of circulating CD193+ B cells lending hope for future vaccine efforts. [ABSTRACT FROM AUTHOR]

Autoimmune polyendocrine syndrome type I (APS‐1) is caused by mutations in the autoimmune regulator (AIRE) gene and characterised clinically by multiple autoimmune manifestations and serologically by autoantibodies against tissue proteins and cytokines. We here hypothesised that lack of AIRE expression in thymus affects blood immune cells and performed whole‐blood microarray analysis (N = 16 APS‐I patients vs 16 controls), qPCR verification, and bioinformatic deconvolution of cell subsets. We identified B cell responses as being downregulated in APS‐1 patients, which was confirmed by qPCR; these results call for further studies on B cells in this disorder. The type I interferon (IFN‐I) pathway was also downregulated in APS‐1, and the presence of IFN antibodies is the likely reason for this mild overall downregulation of the IFN‐I genes in most APS‐1 patients. [ABSTRACT FROM AUTHOR]

Interestingly, in DRB1*03:01 group all HLA-B*08 positive donors showed DRB3*01:01:02 allele, while all HLA-B*08 negative donors and 77.3% of HLA-B*18 positive donors carried DRB3*02:02:01 allele. Our results showed that three HLA alleles were associated with AIN only for patients with anti-HNA-1a specific antibodies; DRB1*01 (OR = 2.63 (1.65-4.21), DRB1*04 (OR = 0.29 (0.15-0.57)) and DQB1*03 (OR = 0.37 (0.23-0.59)), while DRB1*10 (OR = 8.74 (3.29-23.23)) was specific for the remaining group of anti-Fc IIIb antibody positive patients. The minor alleles were significantly over-represented in the subgroup of patients with EIM: 31.2% versus 7.5% in patients without EIM, I p i = 0.001, OR 5.54 for 308*A and 9.3% versus 0.7% in patients without EIM, I p i = 0.04, OR 13.55 for 238*A. No other associations were found in the studied group. A couple of HLA-B alleles showed significant differences when compared between the patient and control groups: HLA-B*15 was increased in patients, while surprisingly, HLA-B*35 showed a significant decrease in people suffering from migraines. The rare HLA-B*39:06:02:01 association with both HLA-C alleles and subsequent haplotype comparison between patient and mother, led to suspicions of possible HLA-C allele dropout in both samples. [Extracted from the article]

Objective: To better characterize the histopathology of oral lichen planus and oral lichenoid lesions and to highlight the differences between them in order to support the clinician in the diagnostic and therapeutic management of such conditions. Subjects and Methods: Fifty‐five patients, clinically diagnosed with oral lichen planus (n = 25) or oral lichenoid lesions (n = 30), were consecutively enrolled in the present study. Subsequently, one blind pathologist reviewed all the biopsy specimens of enrolled subjects following a specific protocol to provide a detailed histopathological description. Demographic, anamnestic, and clinical data were also recorded from all the participants. Patients' data were analysed and compared using the chi‐squared test, to provide distinguishing features between the studied conditions. Results: We found a higher and statistically significant number of eosinophils in the oral lichenoid lesions compared with the oral lichen planus group (p < 0.01), an equally promising result was seen regarding plasma cells, which were more represented (p = 0.05) in the oral lichenoid lesions than in the oral lichen planus cases. No statistically significant differences were detected in demographic, anamnestic and clinical data. Conclusion: A mixed lichenoid inflammatory infiltrate, consisting of eosinophils and plasma cells, could be used as reliable histological features for the diagnosis of oral lichenoid lesions, as long as compared with findings obtained from the patients' history and clinical examination. [ABSTRACT FROM AUTHOR]

Does allergen immunotherapy impact the susceptibility and severity of COVID-19? Allergic asthma (AA) and allergic rhinitis (AR) might be protective against SRAS-CoV-2 infection and progress to severe disease of coronavirus disease 2019 (COVID-19).[1] COVID-19 vaccination was safe and well tolerated in patients receiving allergen immunotherapy (AIT),[[2]] and the adherence to subcutaneous immunotherapy (SCIT) was not affected during COVID-19 pandemic.[4] AIT induces allergen-specific tolerance by attenuating allergen-specific T helper 2 (Th2) cells and inducing regulatory T and B cells and interleukin (IL)-10.[5] We hypothesized that AIT may have a protective impact on the susceptibility and severity of COVID-19. Patients with SCIT had a lower proportion of both at least one dose and completed three doses of COVID-19 vaccines when compared to allergy and non-allergy groups ( I p i = 0.000) (Table S1). [Extracted from the article]

Staphylococcus aureus has been widely reported to be majorly responsible for causing nosocomial infections worldwide. Due to an increase in antibiotic‐resistant strains, the development of an effective vaccine against the bacteria is the most viable alternative. Therefore, in the current work, an effort has been undertaken to develop a novel peptide‐based vaccine construct against S aureus that can potentially evoke the B and T cell immune responses. The fibronectin‐binding proteins are an attractive target as they play a prominent role in bacterial adherence and host cell invasion and are also well conserved among rapidly mutating pathogens. Therefore, highly immunogenic linear B lymphocytes (LBL), cytotoxic T lymphocytes (CTL), and helper T lymphocytes (HTL) epitopes were identified from the antigenic fibronectin‐binding proteins A and B (FnBPA and FnBPB) of S aureus using immunoinformatics approaches. The selected peptides were confirmed to be non‐allergenic, non‐toxic, and with a high binding affinity to the majority of human leukocyte antigens (HLA) alleles. Consequently, the multi‐peptide vaccine construct was developed by fusing the screened epitopes (three LBL, five CTL, and two HTL) together with the suitable adjuvant and linkers. In addition, the tertiary conformation of the peptide construct was modeled and later docked to the Toll‐like receptor 2. Subsequently, a molecular dynamics simulation of 100 ns was employed to corroborate the stability of the designed vaccine‐receptor complex. Besides exhibiting high immunogenicity and conformational stability, the developed vaccine was observed to possess wide population coverage of 99.51% worldwide. Additional in vivo and in vitro validation studies would certainly corroborate the designed vaccine construct to have improved prophylactic efficacy against S aureus. Staphylococcus aureus is a major cause of nosocomial infections worldwide, and the development of an effective vaccine against it is the most viable alternative. This work has been undertaken to develop a novel peptide‐based vaccine construct against S. aureus that can evoke the B and T cell immune responses. [ABSTRACT FROM AUTHOR]

Background: Insight into the pathomechanism of atopic diseases demonstrated a pivotal role of the cytokines interleukin‐4 (IL‐4) and IL‐13, which has spurred the development of tailored therapeutics targeting their common IL‐4 receptor (IL‐4R). However, several aspects of the IL‐4R system remain ill‐defined in humans. Methods: We used multicolor spectral flow cytometry to characterize IL‐4R subunit expression in 28 human immune cell subsets on protein and mRNA levels and assessed their subcellular distribution by applying a specifically adapted protocol that avoided influence of fixation and permeabilization on fluorochrome and antibody performance. In patients, we investigated possible changes in IL‐4Rα distribution before and during treatment with dupilumab, a monoclonal antibody‐targeting IL‐4Rα. Results: Whereas all immune cell subsets investigated expressed IL‐4Rα and common γ chain protein and mRNA, expression of IL‐13Rα1 was restricted to myeloid and B cells. Interestingly, some cells contained considerably more intracellular IL‐4R protein than on their surface. Naive B cells were found to carry the highest levels of IL‐4Rα distributed evenly between surface and intracellular space, whereas IL‐4Rα was found predominantly in intracellular pools in neutrophils. In patients with atopic diseases treated with dupilumab, we observed that engagement of IL‐4Rα by dupilumab resulted in internalization of the antibody and decreased total IL‐4Rα expression. Notably, even after months of treatment not all intracellular IL‐4Rα molecules were occupied by dupilumab, indicating the presence of a "dormant" intracellular IL‐4Rα pool that could be mobilized upon certain extrinsic or intrinsic cues. Conclusion: Collectively, our findings suggest that distinct human immune cell subsets contain surface and intracellular IL‐4R pools, which are differently affected by targeted biologic treatment. [ABSTRACT FROM AUTHOR]

Interstitial cystitis/bladder pain syndrome with Hunner's lesion (HIC) is characterized by chronic inflammation and nerve hyperplasia; however, the pathogenesis of HIC remains a mystery. In this study, we detected both Epstein–Barr virus (EBV) latency infection genes EBNA‐1 and LMP‐1 and EBV lytic infection BZLF‐1 and BRLF‐1 expression in the HIC bladders, indicating the coexistence of EBV persistence and reactivation in the B cells in HIC bladders. Upregulation of EBV‐associated inflammatory genes in HIC bladders, such as TNF‐α and IL‐6, suggests EBV infection is implicated in the pathogenesis of bladder inflammation. Nerve hyperplasia and upregulation of brain‐derived neurotrophic factor (BDNF) were noted in the HIC bladders. Double immunochemical staining and flow cytometry revealed the origin of BDNF to be EBV‐infected B cells. Inducible BDNF expression was noted in B cells upon EBV infection, but not in the T cells. A chromatin immunoprecipitation study revealed BDNF transcription could be promoted by cooperation between EBV nuclear antigens, chromatin modifiers, and B‐cell‐specific transcription. Knockdown of BDNF in EBV‐infected B cells resulted in the inhibition of cell proliferation and viability. Downregulation of phosphorylated SMAD2 and STAT3 after BDNF knockdown may play a role in the mechanism. Implantation of latent EBV‐infected B cells into rat bladder walls resulted in a higher expression level of CD45 and PGP9.5, suggesting tissue inflammation and nerve hyperplasia. In contrast, implantation of BDNF depleted EBV‐infected B cells abrogated these effects. This is the first study to provide insights into the mechanisms underlying the involvement of EBV‐infected B cells in HIC pathogenesis. © 2022 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Problem: Interleukin 35 (IL‐35) is involved in the pathogenesis of endometriosis by suppressing immunoreaction and promoting endometrial cell proliferation. It may also be an essential cytokine in forming the immunosuppressive functions of regulatory B lymphocytes (Bregs). The involvement of Bregs in the pathogenesis of endometriosis has not been previously investigated. In this study, we determined the frequencies of different Breg subpopulations, namely, B10, immature B‐cells, and plasmablasts, and their abilities to produce IL‐35 in women with endometriosis compared to healthy women. Methods: The frequencies of different subpopulations of Bregs producing IL‐35 were measured in the peripheral blood of women with endometriosis (total pool), women with deep infiltration endometriosis (DIE), women with ovarian endometriosis, and healthy women as a control by flow cytometry. Results: We observed a decrease in the percentage of B10 cells and plasmablasts in women with endometriosis and an increase in the percentage of these Breg populations producing IL‐35 in the same experimental group. Interestingly, we also revealed that women with DIE had increased percentages of B10 cells and plasmablasts producing IL‐35. Conclusion: Taken together, our findings are the first to reveal the frequencies of different subpopulations of Bregs producing IL‐35 in women with endometriosis. The results suggest that IL‐35 expression in B lymphocytes could be used as a peripheral marker of endometriosis; however, further studies are needed. [ABSTRACT FROM AUTHOR]