Search

Multiple mechanisms exist by which tumour cells can escape CD95-mediated apoptosis. Previous studies by our laboratory have shown that primary B cells from non-Hodgkin's Lymphoma (B-NHL) were resistant to CD95-induced cell death. In the current study, we have analysed the mechanisms underlying CD95 resistance in primary human lymphoma B cells. We report that FADD (FAS-associated death domain protein) and caspase-8 were constitutively expressed in lymphoma B cells and that the CD95 pathway was blocked upstream to caspase-8 activation. However, caspase-8 was processed and functional after treatment with staurosporine (STS). We found that the expression levels of FLICE (FADD-like interleukin-1 beta-converting enzyme)-Inhibitory Protein (c-FLIP) and Bcl-2-related proteins were heterogeneous in B-NHL cells and were not related to CD95 resistance. Finally, we report the absence of a CD95-induced signalling complex [death-inducing signalling complex (DISC)] in lymphoma B cells, with no FADD and caspase-8 recruitment to CD95 receptor. In contrast, DISC formation was observed in CD95-resistant non-tumoural (NT) B cells. Therefore, we propose that the absence of DISC formation in primary lymphoma B cells may contribute to protect these cells from CD95-induced apoptosis. [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]

Immunoglobulins are the primary mediators of the humoral immune response in fish. Studies of immunoglobulins in fish are particularly important for the immunological control of fish diseases. While immunoglobulin D (IgD) was first discovered in 1965, it remains the least understood member of the antibody family. During evolutionary development from fish to humans, IgD has developed critical immunological functions. However, these immunological functions are not well understood. There are two forms of IgD, membrane IgD (mIgD) and secreted IgD (sIgD). sIgD and mIgD are formed by B lymphocytes through different splicing modes. In this paper, IgD's structure and formation process in fish, the distribution characteristics of IgD on B cells, the mediated signaling pathways, and IgD functions are reviewed. [ABSTRACT FROM AUTHOR]

Aims. This study compared the results obtained by basic immunophenotyping of cerebrospinal fluid (CSF) cells by flow cytometry (FC) to the results of conventional cytology and evaluated the possibility of detailed analyses of CSF B-cell subpopulations. Methods. Samples from 42 patients were examined by conventional cytology (native and/or pre-centrifuged CSF) and FC. The results from 15 patients without evidence of organic neurological disease were used to estimate reference ranges. Results. Pre-centrifugated CSF had significantly higher cell yield on the cytologic slide, but cell subpopulation percentages were altered; the percentage of lymphocytes was significantly higher and monocytes significantly lower compared to both native CSF slides and FC. The percentage of granulocytes was higher in FC compared to cytology. For leukocyte count, the following reference ranges were estimated for Fuchs-Rosenthal chamber (FR) counting and FC, respectively: leukocytes ≤4.7/μL and ≤2.5/μL, lymphocytes ≤4.1/μL and ≤1.8/μL, monocytes ≤1.2/μL and ≤0.9/μL, and granulocytes 0/μL and ≤0.2/μL. The following reference ranges were estimated for basic subpopulations: T-lymphocytes 84.1-100%, B lymphocytes 0.0-1.5%, NK cells 0.0-6.3%, NKT cells 0-9.5%, and CD3+CD4+/CD3+CD8+ 0.8-4.9. Using a volume of 1.2-2.4 mL, the number of B lymphocytes was too low (

Introduction: Among the primary immunodeficiency spectrum, the most common symptomatic type is common variable immunodeficiency (CVID). Aim: This study aims to investigate the relationship of class-switched memory B cells (cSMBCs) (CD19+CD27+IgD-) with the clinical course of coronavirus disease-2019 (COVID-19) in patients with CVID. Material and methods: This single-centre retrospective study evaluated the clinical features, serum immunoglobulin (Ig) levels, and cSMBC levels of 24 polymerase chain reaction (PCR)-confirmed patients with CVID and COVID-19. The COVID-19 disease severity classification, mortality rate, hospitalisation, symptoms, and PCR positivity durations of the patients were recorded. Results: The median age of CVID patients included in the study was 48 (32-58), and 15 of them (62.5%) were female. Disease was severe in 8 (33%) patients, 3 (12.5%) of whom were followed in the intensive care unit and died. The serum IgA, IgM, and CD19+ B lymphocyte cell levels were similar between the mild-moderate and severe disease groups. The cSMBC level was significantly lower in the severe disease group (p = 0.01). The hospitalisation, COVID-19 symptom, and PCR positivity durations were significantly longer in the group with a low cSMBC level (p < 0.05). The cSMBC level was negatively correlated with PCR positivity duration (r = 0.397, p = 0.038). Conclusions: The cSMBC level is related to the clinical course of COVID-19 in patients with CVID. The cSMBC levels has prognostic value in patients with COVID-19. [ABSTRACT FROM AUTHOR]

While cancer has been long recognized as a disease of the genome, the importance of epigenetic mechanisms in neoplasia was acknowledged more recently. The most active epigenetic marks are DNA methylation and histone protein modifications and they are involved in basic biological phenomena in every cell. Their role in tumorigenesis is stressed by recent unbiased large-scale studies providing evidence that several epigenetic modifiers are recurrently mutated or frequently dysregulated in multiple cancers. The interest in epigenetic marks is especially due to the fact that they are potentially reversible and thus druggable. In B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) there is a relative paucity of reports on the role of histone protein modifications (acetylation, methylation, phosphorylation) as compared to acute myeloid leukemia, T-cell ALL, or other hematologic cancers, and in this setting chromatin modifications are relatively less well studied and reviewed than DNA methylation. In this paper, we discuss the biomarker associations and evidence for a driver role of dysregulated global and loci-specific histone marks, as well as mutations in epigenetic modifiers in BCP-ALL. Examples of chromatin modifiers recurrently mutated/disrupted in BCP-ALL and associated with disease outcomes include MLL1, CREBBP, NSD2, and SETD2. Altered histone marks and histone modifiers and readers may play a particular role in disease chemoresistance and relapse. We also suggest that epigenetic regulation of B-cell differentiation may have parallel roles in leukemogenesis. [ABSTRACT FROM AUTHOR]

In a previous paper (Gleichmann, van Elven & van der Veen, 1982), it had been reported that, in contrast to lupus like autoantibodies such as anti-DNA, autoantibodies to mouse thyroglobulin (MTg) were not detectable in serum of F1 mice suffering from a lupus like graft versus host disease (GVHD) (GVH F1). In the present paper, possible explanations for this restricted autoantibody formation during the potent allogeneic stimulation were investigated. The main question was whether the natural level of circulating MTg was too low to induce the formation of anti-MTg antibodies in GVH F1 mice. Existence, in the F1 mice studied, of B cells capable of producing anti-MTg antibodies was demonstrated by injection of lipopolysaccharide (LPS) and exogeneous MTg. However, MTg injected into various F1 mice at the onset of the GVH reaction (GVHR) failed to overcome the lack of antibody formation to MTg even though the GVHR led to a severe lupus like disease. Furthermore, adult thymectomy (ATx) of either the recipients, the donors, or both also did not break tolerance to MTg during the GVHR, irrespective of administration of exogeneous MTg. Thus, neither intravenous injection of MTg nor ATx, designed to remove T suppressor (Ts) cells, is adequate to enable an autoantibody response to MTg during lupus like GVHD. Hence, the non-specific T cell help that causes lupus like GVHD seems to be intrinsically insufficient to trigger the Tg reactive B cells. We suggest that globular proteins, such as Tg, require specific T cell help. In the presence of only non-specific T help, self-antigens such as DNA seem to be more apt than globular proteins to provide an effective signal 1 to the corresponding autoreactive B cells. [ABSTRACT FROM AUTHOR]

Immune cells have an uncertain function during the progression of extranodal natural killer/T‐cell lymphoma (ENKTL). The present study determined the distribution, phenotype, and clinical significance of B lymphocytes in ENKTL. Immunohistochemistry indicated high infiltration of CD20+ B lymphocytes in the tumour tissues of 40% of the patients, and that a high infiltration correlated with better overall survival. Moreover, B lymphocytes had an active mature phenotype in situ and suppressed the proliferation of ENKTL cells in vitro. These results suggest that tumour infiltration of CD20+ B lymphocytes may be a new prognostic indicator for patients with ENKTL. [ABSTRACT FROM AUTHOR]

The mechanisms underlying the immune response to coronavirus disease 2019 (COVID-19) and the recovery process have not been fully elucidated. The aim of the study was to analyze leukocyte subpopulations in patients at significant time points (at diagnosis, and 3 and 6 months after infection) selected according to the analysis of changes in the lungs by the CT classification system, considering the severity of the disease. The study groups consisted of severe and non-severe COVID-19 patients. There was a significant decrease in CD8+ T cells, NK and eosinophils, with an increasing percentage of neutrophils during hospitalization. We noticed lower levels of CD4 and CD8 T lymphocytes, eosinophils, basophils, and CD16+ monocytes and elevated neutrophil levels in severe patients relative to non-severe patients. Three months after infection, we observed higher levels of basophils, and after 6 months, higher CD4/CD8 ratios and T cell levels in the severe compared to non-severe group. Non-severe patients showed significant changes in the leukocyte populations studied at time of hospitalization and both within 3 months and 6 months of onset. The CT CSS classification with parameters of the flow cytometry method used for COVID-19 patients determined changes that proved useful in the initial evaluation of patients. [ABSTRACT FROM AUTHOR]

Abstract In order to elucidate the influence of T lymphocytes subpopulations on B lymphocytes immune response, in this paper, CD4-1+, CD4-2+, CD8+ T lymphocytes and B lymphocytes responses to thymus-independent (TI) or thymus-dependent (TD) antigen plus immunosuppressant were investigated in flounder (Paralichthys olivaceus). The results showed that in LPS-immunized group, the percentages of CD4-1+, CD4-2+, CD8β+ T (PCD4-1+ T, PCD4-2+ T and PCD8β+ T) lymphocytes in peripheral blood leucocytes (PBLs) had no significant variations, the percentages of IgM+ B (PIgM+ B) lymphocytes and LPS-specific antibodies (LA) significantly increased and peaked at 3rd or 4th week post-injection; CsA had no inhibition on both T/B lymphocytes and LA; RaPa only suppressed the PIgM+ B lymphocytes and LA, and the inhibition maximum (Imax) were about 35% and 20%, respectively. In KLH-immunized group, the PCD4-1+, PCD4-2+ and PCD8β+ T lymphocytes significantly increased and peaked at 3rd or 5th day, successively the PIgM+ B lymphocytes and KLH-specific antibodies (KA) significantly increased to the peak at 5th week; the PCD4-1+, PCD4-2+ T and PIgM+ B lymphocytes and LA were inhibited significantly by both CsA and RaPa, and the Imax on them were 13%–33%, 11%–25%, 19%–34%, 22%–26%, respectively, while the PCD8β+ T lymphocytes showed no significant suppression. The results indicated that the suppression of PIgM+ B lymphocytes in KLH + CsA group was not directly derived from CsA, but due to the suppression of T lymphocytes, especially CD4+ T lymphocytes subpopulations. The results showed for the first time that, similar to higher vertebrates, T lymphocytes didn't respond to TI antigen, moreover, T lymphocyte subpopulations had a regulation on the immune response of B lymphocyte for TD antigen in flounder. Highlights • KLH activated CD4-1+, CD4-2+, CD8+ T and B lymphocytes responses. • LPS only induced B lymphocytes response and antibodies production. • Cyclosporine A (CsA) specifically inhibited T lymphocytes. • CD4-1+, CD4-2+ T lymphocytes influenced the response of B lymphocytes for TD antigen. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) has traditionally been considered to be a T-cell-mediated disease. However, there is an increasing body of evidence for the involvement of B cells and autoantibodies in the pathology of this disease, providing a rationale for treatments directed against B cells. In this paper we summarize evidence for the key role of B cells in the immunopathology of MS and review data supporting the use of a novel B-cell targeted therapy, atacicept, in this condition. Atacicept is a human recombinant fusion protein that comprises the binding portion of a receptor for both BLyS (B-Lymphocyte Stimulator) and APRIL (A PRoliferation-Inducing Ligand), two cytokines that have been identified as important regulators of B-cell maturation, function and survival. Atacicept has shown selective effects on cells of the B-cell lineage, acting on mature B cells and blocking plasma cells and late stages of B-cell development while sparing B-cell progenitors and memory cells. The efficacy of atacicept in animal models of autoimmune disease and the biological activity of atacicept in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) has been demonstrated. Clinical studies were initiated to investigate the safety, tolerability and efficacy of atacicept in patients with MS. An unexpected increase in inflammatory activity in one of the trials, however, led to suspension of all atacicept trials in MS. [ABSTRACT FROM PUBLISHER]

Rheumatoid arthritis (RA) is represents the most common chronic inflammatory joint disease and is still a major medical challenge because of unsolved issues related to the etiologic and pathogenetic questions. Intensive research has been conducted over the last years that focused on the inappropriate activation of the immune system: although T cells have long been deemed to play a central role in the origin and propagation of joint inflammation, data accumulated so far have widened this perspective recognizing the contribution of other cells, as well as the major histocompatibility complex class II proteins and a composite set of costimulatory signals responsible for the production of proinflammatory cytokines and other soluble mediators implicated in tissue destruction typical of the disease. This paper will provide an insight into the immune system in RA, dissecting cellular and humoral aspects both in serum and in synovium of patients. [ABSTRACT FROM AUTHOR]

B-Cell chronic lymphocytic leukemia (B-CLL) is an incurable disease that is relatively common among aging Caucasians. Patients with this leukemia can be divided into prognostic categories using clinical staging parameters, as well as molecular features [presence or absence of IgVH mutations in rearranged VHDJH segments that code for the leukemic B cell's receptor for antigen (BCR)]. In addition, the deduced amino acid structure of the BCRs from patients that fall into different prognostic categories is shared, to varying degrees, within these groups. In this paper, the molecular features of the genes that code for the BCRs of B-CLL patients are reviewed, and these are comapred to antibodies of known specificity. These comparisons suggest that the BCRs of many cases resemble autoantibodies, and in some cases, antibodies to microbial antigens. Antigen-binding analyses confirm these impressions, and also indicate that polyreactivity appears to distinguish cases with worse clinical outcomes differ from those with better outcomes. The persistence of autoreactivity and polyreactivity is somewhat surprising, because IgV DNA sequence analyses suggest that many of the B cells that become leukemic have undergone one form or another of receptor editing. Thus, B-CLL appears to be a disease of B-cell clones that have undergone various types of receptor reconfiguration and yet retain inappropriate antigen-binding properties. [ABSTRACT FROM AUTHOR]

Peripheral blood transcriptome is a highly promising area for biomarker development. However, transcript abundances (TA) in these cell mixture samples are confounded by proportions of the component leukocyte subpopulations. This poses a challenge to clinical applications, as the cell of origin of any change in TA is not known without prior cell separation procedure. We developed a framework to develop a cell-type informative TA biomarkers which enable determination of TA of a single cell-type (B lymphocytes) directly in cell mixture samples of peripheral blood (e.g., peripheral blood mononuclear cells, PBMC) without the need for subpopulation separation. It is applicable to a panel of genes called B cell informative genes. Then a ratio of two B cell informative genes (a target gene and a stably expressed reference gene) obtained in PBMC was used as a new biomarker to represent the target gene expression in purified B lymphocytes. This approach, which eliminates the tedious procedure of cell separation and directly determines TA of a leukocyte subpopulation in peripheral blood samples, is called the Direct LS-TA method. This method is applied to gene expression datasets collected in influenza vaccination trials as early predictive biomarkers of seroconversion. By using TNFRSF17 or TXNDC5 as the target genes and TNFRSF13C or FCRLA as the reference genes, the Direct LS-TA B cell biomarkers were determined directly in the PBMC transcriptome data and were highly correlated with TA of the corresponding target genes in purified B lymphocytes. Vaccination responders had almost a 2-fold higher Direct LS-TA biomarker level of TNFRSF17 (log 2 SMD = 0.84, 95% CI = 0.47–1.21) on day 7 after vaccination. The sensitivity of these Direct LS-TA biomarkers in the prediction of seroconversion was greater than 0.7 and area-under curves (AUC) were over 0.8 in many datasets. In this paper, we report a straightforward approach to directly estimate B lymphocyte gene expression in PBMC, which could be used in a routine clinical setting. Moreover, the method enables the practice of precision medicine in the prediction of vaccination response. More importantly, seroconversion could now be predicted as early as day 7. As the acquired immunology pathway is common to vaccination against influenza and COVID-19, these biomarkers could also be useful to predict seroconversion for the new COVID-19 vaccines. [ABSTRACT FROM AUTHOR]

The fish immune system is extremely complex and has considerable adaptive potential. In Osteichthyes, the system is formed by lymphopoietic organs which are important for the differentiation and maturation of the immune system cells. These organs include the anterior kidney (phronephros), the thymus, the spleen, the posterior kidney (mesonephros), and mucosa-associated lymphoid tissues (MALT). Apart from the lymphocytic organs and the MALT system, the immune system components include defensive cells and their products. Those identified in fish include, inter alia, monocytes/macrophages, melanomacrophages, neutrophilic granulocytes, thrombocytes, B cells, plasma cells, and T cells. The roles of the individual components of the organisation of the immune system, the organs, and lymphoid tissue as well as the constituents conditioning the innate and adaptive immunity mechanisms are considered equally important, especially in the context of functional interdependence. The progress in the exploration of the processes of specific humoral immunity in Osteichthyes and the possibilities of their practical application is increasingly promising in view of the expected need for protection of fish against diseases. The paper discusses selected issues concerning recent knowledge about haematopoiesis of B cells, plasmablasts, plasma cells, and immunoglobulins (IgM, IgD, IgT/IgZ). [ABSTRACT FROM AUTHOR]

T and B lymphocytes are closely related to immunization and pathogen infection. Our previous study confirmed the CD3 + , CD4-1 + , CD4-2 + , CD8β + T lymphocytes and IgM + B lymphocytes presented in the peripheral blood leukocytes (PBLs) of flounder ( Paralichthys olivaceus ), in this paper, the variations of T and B lymphocytes of flounder after Hirame novirhabdovirus (HIRRV) infection or immunization were investigated. The flounders were injected with live or inactivated HIRRV, then the percentages of T and B lymphocytes in PBLs were analyzed by Flow cytometry (FCM), total antibodies and HIRRV-specific antibodies in serum were detected by Enzyme-linked immunosorbent assay (ELISA), and expression of twelve immune-related genes in the head kidneys were determined using q-PCR. The results showed that the percentages of CD3 + , CD4-1 + , CD4-2 + , CD8β + T lymphocytes and IgM + B lymphocytes significantly increased in both infection and immunization groups, in infection group they decreased rapidly after the peak and significantly lower than control levels at the end of infection, in immunization group they went down steadily to the control levels at the end of immunization. The total antibodies and HIRRV-specific antibodies increased first and peaked on the 7 th day post infection and on the 14 th day post immunization, respectively, then gradually decreased to the control levels. Additionally, twelve immune-related genes were up-regulated in both groups. These results demonstrated that the HIRRV induced both humoral and cellular immunity of flounder, the lymphocytes varied more sharply in infection group than those in immunization group and CD8 + T lymphocytes responded much more than CD4 + T lymphocytes to HIRRV antigen. [ABSTRACT FROM AUTHOR]

During a primary immune response generally two classes of antibody are produced, immunoglobulin M (IgM) and immunoglobulin G (IgG). It is currently thought that some lymphocytes which initially produce IgM switch to the production of IgG with the same specificity for antigen. During a secondary immune response IgG is the predominant antibody made throughout the response. In this paper we address the question of why such apparently complicated modes of response should have been adapted by evolution. We construct mathematical models of the immune response to growing antigens which incorporate complement dependent cell lysis. By comparing the times required to eliminate antigen we show that under certain conditions it is advantageous for an animal to switch some of its lymphocytes from IgM to IgG production during a primary response, but yet to secrete only IgG during a secondary response. The sensitivity of such a conclusion to parameter variations is studied and the biological basis and implications of our models are fully discussed. [ABSTRACT FROM AUTHOR]

IL-4 has previously been shown to stimulate motile responses in murine B lymphocytes. This was studied as acquisition of motile morphology and migration through filters in microchemotaxis chambers. In this paper, we investigated IL-4-stimulated migration of B cells into gels of native collagen fibers, which may be a more physiologically relevant assay. When IL-4 was present in the gel and/or in the medium above, B cells were able to invade the collagen gel. Migration was dependent on the dose of IL-4 and was optimal after 45 h of incubation. It appeared that IL-4 acted by inducing both chemokinesis and chemotaxis. Fibronectin (FN) was found to be an important factor for B cell locomotion, since low concentrations of FCS or FN in the gel matrix greatly improved migration. B cell locomotion was inhibited by antibodies specific for β1, α4 and α5 integrins, indicating the presence of integrin-extracellular matrix (ECM) interactions in lymphocyte motility responses. Migration was not associated with an up-regulatlon of β1, α4 or α5 integrins. The adhesion between substrate and cells is likely to be of low affinity, since IL-4-stimulated, as well as non-stimulated B cells, did not adhere to ECM-coated culture wells. Our data suggest that transient interactions between integrins and the ECM matrix may favour B cell migration. [ABSTRACT FROM PUBLISHER]

Using the system of morphometric analysis described in this paper, human peripheral blood T and B lymphocytes, labeled with specific surface markers, can be compared on different analytical levels. They show differences in their surface and the eccentricity of cells, in the relative surfaces occupied by peripheral and central condensed chromatin, in the average surface of the central chromatin clumps and in the number of perichromatin granules per nuclear surface. The morphometric analysis reveals the importance of examining the nuclear and the surface parameters in the characterization of lymphocytes, confirming that a detailed analysis of the nuclear characteristics can contribute to the identification of T and B lymphocytes by transmission electron microscopy. [ABSTRACT FROM AUTHOR]

Introduction: B cells, which have long been thought to be minor players in the development of anti-tumor responses, have been implicated as key players in lung cancer pathogenesis and response to checkpoint blockade in patients with lung cancer. Enrichment of late-stage plasma and memory cells in the tumor microenvironment has been shown in lung cancer, with the plasma cell repertoire existing on a functional spectrum with suppressive phenotypes correlating with outcome. B cell dynamics may be influenced by the inflammatory microenvironment observed in smokers and between LUAD and LUSC. Methods: Here, we show through high-dimensional deep phenotyping using mass cytometry (CyTOF), next generation RNA sequencing and multispectral immunofluorescence imaging (VECTRA Polaris) that key differences exist in the B cell repertoire between tumor and circulation in paired specimens from lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC). Results: In addition to the current literature, this study provides insight into the in-depth description of the B cell contexture in Non-Small Cell Lung Cancer (NSCLC) with reference to broad clinico-pathological parameters based on our analysis of 56 patients. Our findings reinforce the phenomenon of B-cell trafficking from distant circulatory compartments into the tumour microenvironment (TME). The circulatory repertoire shows a predilection toward plasma and memory phenotypes in LUAD however no major differences exist between LUAD and LUSC at the level of the TME. B cell repertoire, amongst other factors, may be influenced by the inflammatory burden in the TME and circulation, that is, smokers and non-smokers. We have further clearly demonstrated that the plasma cell repertoire exists on a functional spectrum in lung cancer, and that the suppressive regulatory arm of this axis may play a significant role in determining postoperative outcomes as well as following checkpoint blockade. This will require further long-term functional correlation. Conclusion: B and Plasma cell repertoire is very diverse and heterogeneous across different tissue compartments in lung cancer. Smoking status associates with key differences in the immune milieu and the consequent inflammatory microenvironment is likely responsible for the functional and phenotypic spectrum we have seen in the plasma cell and B cell repertoire in this condition. [ABSTRACT FROM AUTHOR]

Phosphoinositide 3-kinase delta (PI3Kd) plays key roles in normal B cell activation and is chronically activated in malignant B cells. Targeting of PI3Kd using FDAapproved drugs Idelalisib or Umbralisib has shown efficacy in treatment of multiple B cell malignancies. Duvelisib, an inhibitor targeting both PI3Kd and PI3Kg (PI3Kdgi) has also been used for treatment of several leukemias and lymphomas and was suggested to offer potential additional benefits in supressing T cell and inflammatory responses. Transcriptomics analyses indicated that while most B cell subsets predominantly express PI3Kd, plasma cells upregulate PI3Kg. We thus assessed whether PI3Kdgi treatment can impact chronic B cell activation in the context of an autoantibody-mediated disease. Using the TAPP1R218LxTAPP2R211L (TAPP KI) mouse model of lupus-like disease driven by dysregulated PI3K pathway activity, we performed 4 week PI3Kdgi treatments and found significant reduction in CD86+ B cells, germinal center B cells, follicular helper T cells and plasma cells in multiple tissues. This treatment also significantly attenuated the abnormally elevated serum levels of IgG isotypes observed in this model. The profile of autoantibodies generated was markedly altered by PI3Kdgi treatment, with significant reductions in IgM and IgG targeting nuclear antigens, matrix proteins and other autoantigens. Kidney pathology was also impacted, with reduced IgG deposition and glomerulonephritis. These results indicate that dual inhibition of PI3Kd and PI3Kg can target autoreactive B cells and may have therapeutic benefits in autoantibody-mediated disease. [ABSTRACT FROM AUTHOR]

Introduction: The human immune system contains cells with either effector/ memory or regulatory functions. Besides the well-established CD4 +CD25hiCD127lo regulatory T cells (Tregs), we and others have shown that B cells can also have regulatory functions since their frequency and number are increased in kidney graft tolerance and B cell depletion as induction therapy may lead to acute rejection. On the other hand, we have shown that CD28-CD8+ T cells represent a subpopulation with potent effector/memory functions. In the current study, we tested the hypothesis that kidney allograft rejection may be linked to an imbalance of effector/memory and regulatory immune cells. Methods: Based on a large cohort of more than 1000 kidney graft biopsies with concomitant peripheral blood lymphocyte phenotyping, we investigated the association between kidney graft rejection and the percentage and absolute number of circulating B cells, Tregs, as well as the ratio of B cells to CD28-CD8+ T cells and the ratio of CD28-CD8+ T cells to Tregs. Kidney graft biopsies were interpreted according to the Banff classification and divided into 5 biopsies groups: 1) normal/subnormal, 2) interstitial fibrosis and tubular atrophy grade 2/3 (IFTA), 3) antibody-mediated rejection (ABMR), 4) T cell mediated-rejection (TCMR), and 5) borderline rejection. We compared group 1 with the other groups as well as with a combined group 3, 4, and 5 (rejection of all types) using multivariable linear mixed models. Results and discussion: We found that compared to normal/subnormal biopsies, rejection of all types was marginally associated with a decrease in the percentage of circulating B cells (p=0.06) and significantly associated with an increase in the ratio of CD28-CD8+ T cells to Tregs (p=0.01). Moreover, ABMR, TCMR (p=0.007), and rejection of all types (p=0.0003) were significantly associated with a decrease in the ratio of B cells to CD28-CD8+ T cells compared to normal/subnormal biopsies. Taken together, our results show that kidney allograft rejection is associated with an imbalance between immune cells with effector/memory functions and those with regulatory properties. [ABSTRACT FROM AUTHOR]

Follicular lymphoma (FL) is an indolent disease, characterized by a median life expectancy of 18-20 years and by intermittent periods of relapse and remission. FL frequently transforms into the more aggressive diffuse large B cell lymphoma (t-FL). In previous studies, the analysis of immunoglobulin heavy chain variable region (IgHV) genes in sequential biopsies from the same patient revealed two different patterns of tumor clonal evolution: direct evolution, through acquisition of additional IgHV mutations over time, or divergent evolution, in which lymphoma clones from serial biopsies independently develop from a less-mutated common progenitor cell (CPC). Our goal in this study was to characterize the somatic hypermutation (SHM) patterns of IgHV genes in sequential FL samples from the same patients, and address the question of whether the mutation mechanisms (SHM targeting, DNA repair or both), or selection forces acting on the tumor clones, were different in FL samples compared to healthy control samples, or in late relapsed/transformed FL samples compared to earlier ones. Our analysis revealed differences in the distribution of mutations from each of the nucleotides when tumor and nontumor clones were compared, while FL and transformed FL (t-FL) tumor clones displayed similar mutation distributions. Lineage tree measurements suggested that either initial clone affinity or selection thresholds were lower in FL samples compared to controls, but similar between FL and t-FL samples. Finally, we observed that both FL and t-FL tumor clones tend to accumulate larger numbers of potential N-glycosylation sites due to the introduction of new SHM. Taken together, these results suggest that transformation into t-FL, in contrast to initial FL development, is not associated with any major changes in DNA targeting or repair, or the selection threshold of the tumor clone. [ABSTRACT FROM AUTHOR]

Immunodisruptive homeostasis is recognized in allergic disorders. The mechanism of restoration of immunologic homeostasis in the body is not fully understood. Galectin‐9 (Gal9) and CD22 have immune regulatory functions. The goal of this study is to test the role of CD22+ CD9+ B regulatory cells in immune homeostasis the body. A much smaller amount of IL‐10 in B10 cells was detected in patients with allergic rhinitis (AR) in contrast to healthy subjects. The IL‐10 expression levels in B10 cells were positively correlated with the CD22 expression. CD22 mediated the effects of Gal9 on the enhanced expression of IL‐10 in AR B10 cells. Gal9 overcame the refractory induction of IL‐10 in B‐cells of AR subjects. The immune regulatory ability of AR B10 cells could be restored by Gal9. Combination of Gal9 and SIT induced and activated antigen‐specific B10 cells. The B10 cells of Gal9/specific immunotherapy‐treated AR mice showed immunosuppressive functions on T‐cell activities and induction of type 1 regulatory T cells in an antigen‐specific manner. Administration of Gal9 potentiated the effects of specific immunotherapy in mice with AR. In summary, a fraction of regulatory B cells, the CD19+ CD22+ CD9+ B cells, was characterized in the present study. CD22 mediates the effects of Gal9 to promote immunotherapy for allergic diseases by inducing B10 cells. In an antigen‐specific manner, the B10 cells suppressed CD4+ T cell activities, and alleviated experimental AR. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) remains one of the most important health challenges worldwide. Control of the TB epidemic has not yet been achieved because of the lack of an effective vaccine and rapid and sensitive diagnostic approaches, as well as the emergence of drug-resistant forms of M. tuberculosis. Cellular immunity has a pivotal role against M. tuberculosis infection, but the role of humoral immunity is still controversial. We analyzed the frequency, absolute counts, and phenotypic and functional subsets of B lymphocytes in the peripheral blood of patients with active TB and subjects with latent infection compared to healthy donors. Moreover, we analyzed serum levels of total Ig and their IgA, IgM, and IgG isotypes and the titers of preexisting antibodies against a pool of common viral pathogens. FlowCT and unsupervised clusterization analysis show that patients with active TB and LTBI subjects have modest non-significant reduction in the numbers of circulating B lymphocytes as compared to healthy donors. Moreover, LTBI subjects had high percentages of atypical B cell population and lower percentages of naive and switched memory B cells. These findings were supported by gene expression and GSEA analysis. Moreover, there were no differences between active TB patients, LTBI subjects and HD, either in serum levels of total Ig isotypes or in preexisting IgG antibody titers, to ten different antigens from eight common pathogenic viruses, clearly demonstrating that either active or latent M. tuberculosis infection preserves the antibody production capacity of long-lived plasma cells. Thus, our results agree with previous studies reporting unaltered B cell frequencies in the blood of active TB patients and LTBI individuals as compared to healthy controls. [ABSTRACT FROM AUTHOR]

GPR174 is abundantly expressed in B and T lymphocytes and has a role in restraining T cell responses, but the function of GPR174 in B cells is less clear. Here we report that upon in vitro culture B cells undergo a spontaneous GPR174-dependent activation process that is associated with marked changes in gene expression, including upregulation of Cd86, Nr4a1, Ccr7, and phosphodiesterases. B cells lacking Gαsshowa block in induction of the GPR174-dependent program. Spontaneous up-regulation of CD86 in cultured B cells is dependent on protein kinase A. Both GPR174- and Gαs-deficient B cells show enhanced survival in culture. In vivo, GPR174 contributes to NUR77 expression in follicular B cells and is needed for establishing a marginal zone compartment of normal size. Treatment of mice with lysophosphatidylserine (lysoPS), a GPR174 ligand, is suicient to promote CD86 up-regulation by follicular B cells. hese indings demonstrate that GPR174 can signal via Gαs to modulate B cell gene expression and show this can occur in vivo in response to lysoPS. Additionally, the findings illuminate a pathway that might be targeted to improve systems for the in vitro study of B cell responses. [ABSTRACT FROM AUTHOR]

Newly identified PD-1hiCXCR5–CD4+ T-cells, termed as peripheral helper T-cells (Tph), have been found elevated and playing a pathogenic role in some autoimmune diseases like systemic lupus erythematosus (SLE) and rheumatic arthritis (RA). However, the potential role of Tph-cells in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) remains unclear. Here, we explored the potential clinical significance of circulating Tph-cells in the pathogenesis of AAV. Comparing 32 active AAV patients and 18 age- and sex-matched healthy controls (HCs), we found that the frequency of circulating Tph-cells was significantly expanded in active AAV patients. Besides, programmed death 1 (PD-1) expression on the surface of Tph-cells was significantly up-regulated in active AAV patients. Importantly, the frequency of circulating Tph-cells was greatly decreased in AAV patients after receiving treatment. Tph-cells frequency was positively correlated with the Birmingham Vasculitis Activity Score (BVAS), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), neutrophil lymphocyte ratio (NLR), and cellular crescent in active AAV patients, but negatively correlated with fibrosus crescent. Tph-cells frequency was also positively correlated with naïve B-cells, serum concentration of MPO-ANCAs, serum tumor necrosis factor-α (TNF-α), IL-4, IL-21, and IL-12. However, serum IL-10 exhibited a negative correlation with circulating Tph-cells in active AAV patients. These results demonstrate that circulating Tph-cells are greatly expanded in active AAV patients and are positively associated with serum MPO-ANCAs and disease activity, thus contributing to the pathogenesis of AAV. The role of newly identified peripheral helper T cells (Tph) in ANCA-associated vasculitis (AAV) remains largely unknown, although they have been found elevated and playing pathogenic role in some autoimmune disease including SLE and RA. In this study, Liu et al found that Tph cells were greatly expanded in active AAV patients and decreased after treatment with methylprednisolone and cyclophosphamide, and they were positively correlated with vasculitis activity index, serum concentration of MPO-ANCA, IL-4 and IL-21. These results indicate that Tph cells may play a pathogenic role in AAV through promoting plasma cell activation possibly by secreting IL-4 and IL-21. [ABSTRACT FROM AUTHOR]

Aims In pre-clinical models of acute myocardial infarction (MI), mature B cells mobilize inflammatory monocytes into the heart, leading to increased infarct size and deterioration of cardiac function, whilst anti-CD20 antibody-mediated depletion of B cells limits myocardial injury and improves cardiac function. Rituximab is a monoclonal anti-CD20 antibody targeted against human B cells. However, its use in cardiovascular disease is untested and is currently contraindicated. Therefore, we assessed the safety, feasibility, and pharmacodynamic effect of rituximab given to patients with acute ST-elevation MI (STEMI). Methods and results Rituximab in patients with acute ST-elevation myocardial infarction (RITA-MI) was a prospective, open-label, dose-escalation, single-arm, phase 1/2a clinical trial, which tested rituximab administered as a single intravenous dose in patients with STEMI within 48 h of symptom onset. Four escalating doses (200, 500, 700, and 1000 mg) were used. The primary endpoint was safety, whilst secondary endpoints were changes in circulating immune cell subsets including B cells, and cardiac and inflammatory biomarkers. A total of 24 patients were dosed. Rituximab appeared well tolerated. Seven serious adverse events were reported, none of which were assessed as being related to the rituximab infusion. Rituximab caused a mean 96.3% (95% confidence interval 93.8–98.8%) depletion of circulating B cells within 30 min of starting the infusion. Maximal B-cell depletion was seen at Day 6, which was significantly lower than baseline for all doses (P  < 0.001). B-cell repopulation at 6 months was dose-dependent, with modulation of returning B-cell subsets. Immunoglobulin (IgG, IgM, and IgA) levels were not affected during the 6 months of follow-up. Conclusions A single infusion of rituximab appears safe when given in the acute STEMI setting and substantially alters circulating B-cell subsets. We provide important new insight into the feasibility and pharmacodynamics of rituximab in acute STEMI, which will inform further clinical translation of this potential therapy. Clinical trial registration NCT03072199 at https://www.clinicaltrials.gov/ [ABSTRACT FROM AUTHOR]

Abstract: Signalling through the B cell antigen receptor (BCR) is required for peripheral B lymphocyte maturation, maintenance, activation and silencing. In mature B cells, the antigen receptor normally consists of two isotypes: membrane IgM and IgD (mIgM, mIgD). Although the signals initiated from both isotypes differ in kinetics and intensity, in vivo, the BCR of either isotype seems to be able to compensate for the loss of the other, reflected by the mild phenotypes of mice deficient for mIgM or mIgD. Thus, it is still unclear why mature B cells need expression of mIgD in addition to mIgM. In the present paper, we used the B cell line Bcl1 and investigated the isotype-specific antigen internalization in dependence of co-stimulation of the reciprocal isotype and analysed whether the signal initiated from mIgM is modulated through signalling from mIgD and vice versa. We clearly showed that cross-linkage of mIgM decreases the rate of mIgD mediated antigen internalization and interpret this influence as a unilateral mIgM mediated control on signals initiated at mIgD. [Copyright &y& Elsevier]

Peripheral helper T (Tph) cells, phenotypically PD-1hiCXCR5-CD4+, are a recently identified Th cell subset that relates to several autoimmune diseases. Contrary to PD-1hiCXCR5+CD4+ follicular helper T (Tfh) cells, Tph cells are not located in lymphoid organs but accumulate in inflamed tissues. This study investigated Tph cells to determine their involvement in dermatomyositis (DM). The frequency of circulating Tph and Tfh cells was evaluated by flow cytometry at baseline and after glucocorticoid treatment. The expression of Tph and B cells was determined in muscle tissue by immunohistochemistry (IHC). Further, the correlations between circulating Tph cells and clinical characteristics were investigated. Flow cytometry revealed that circulating Tph and Tfh cells were decreased in peripheral blood of DM patients compared with healthy controls (HCs). However, the muscular expression of Tph and B cells was upregulated in patients with DM compared to that in the controls by IHC. Interestingly, the increased B cells accumulated around Tph cells in infiltrated lesions. The frequency of circulating Tph cells was positively correlated with Tfh cells, CD3+ T cells, CD4+ T cells, and CD8+ T cells, whereas negatively correlated with erythrocyte sedimentation rate (ESR), interleukin (IL)-6, and IL-10 levels. Furthermore, the abnormal circulating Tph cells in peripheral blood were recovered after glucocorticoid treatment. These results indicate that Tph cells might be involved in the immunopathogenesis of DM and therefore might provide novel insight for the development of DM therapies. [ABSTRACT FROM AUTHOR]

This paper evaluates the expression and functional significance of PPAR-γ on human B cells. Recent interest in PPAR-γ has focused on its adipogenic effects on non-bone marrow-derived cells. PPAR-γ agonists also have been proposed as anti-inflammatory agents owing to inhibition of NF-κB activation. We report herein the first study evaluating PPAR-γ expression and functional significance in human B lineage cells. Interestingly, normal human B cells and a variety of B lymphoma cells (e.g., Daudi, Ramos, and Raji) express PPAR-γ protein as determined by immunocytochemistry. The expression of 80-kDa PPAR-γ on human B lymphocytes and B lymphomas was confirmed by Western blot analysis. 15-Deoxy-Δ12,14-PGJ2 (15d-PGJ2), a natural PPAR-γ agonist, has a dose-dependent antiproliferative and cytotoxic effect on normal and malignant B cells as shown by [3H]thymidine and MTT assays. Only PPAR-γ agonists (thiazolidinediones) and not PPAR-α agonists mimicked the effect of 15d-PGJ2 on B lineage cells, indicating that the mechanism by which 15d-PGJ2 negatively affects B lineage cells involves, in part, PPAR-γ. The mechanism whereby PPAR-γ agonists induce cytotoxicity is via apoptosis as shown by Annexin V staining and as confirmed by DNA fragmentation detected using the TUNEL assay. This is the first study evaluating PPAR-γ expression and its significance on human B lymphocytes. PPAR-γ agonists may serve as a counterbalance to the stimulating effects of other prostaglandins, namely PGE2, which promotes B cell immunoglobulin class switching. Finally, the use of prostaglandins such as 15d-PGJ2 and synthetic PPAR-γ agonists to induce apoptosis in B lineage cells may lead to the development of novel therapies for potentially fatal B lymphomas. [Copyright &y& Elsevier]