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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]

Different studies over the last decade have linked the B cell-attracting chemokine CXC ligand 13 ( CXCL13) to the autoimmune disease systemic lupus erythematosus ( SLE). A pathogenetic role of this chemokine for disease manifestation in SLE was described initially in mouse models for SLE. Mechanisms of CXCL13 actions were also identified in SLE patients. Moreover, various clinical studies have identified CXCL13 serum levels as a useful biomarker in patients with SLE of different ethnicities for disease activity. In addition, CXCL13 seems to be a promising marker for the diagnosis of lupus nephritis, one of the most severe complications of SLE. However, its exact place within the mechanisms that lead to SLE remains to be defined. Further research is needed to resolve more details of the pathomechanism and the signalling pathway of CXCL13 in SLE. Blocking CXCL13 or the signal pathways of CXCL13 is seen as a promising therapeutic approach for SLE and will be addressed in the near future. This review summarizes all papers that linked CXCL13 to SLE and highlights its importance in the pathogenesis and diagnosis of SLE [ABSTRACT FROM AUTHOR]

Previous studies have shown the down-regulating in vitro effect of cocoa flavonoids on lymphocyte and macrophage activation. In the present paper, we report the capacity of a long-term rich cocoa diet to modulate macrophage cytokine secretion and lymphocyte function in young rats. Weaned rats received natural cocoa (4% or 10% food intake), containing 32 mg flavonoids/g, for 3 weeks. Spleen immune function was then evaluated through the analysis of lymphocyte composition, their proliferative response and their ability to secrete cytokines and Ig. In addition, the status of activated peritoneal macrophages was established through tumour necrosis factor (TNF)-α secretion. The richest cocoa diet (10%) caused a reduction of TNF-α secretion by peritoneal macrophages showing anti-inflammatory activity. Similarly, although a 10% cocoa diet increased lymphocyte proliferation rate, it down-regulated T helper 2 (Th2)-related cytokines and decreased Ig secretion. These changes were accompanied by an increase in spleen B cell proportion and a decrease in Th cell percentage. In summary, these results demonstrate the functional activity of a cocoa-high dosage in down-regulating the immune response that might be beneficial in hypersensitivity and autoimmunity. [ABSTRACT FROM AUTHOR]

The importance of B cells and their critical role in the maintenance of health through generation of antibody-mediated immune protection is undoubted. However, the differences between the responses of B cells with different surface phenotypes in different microanatomical sites as well as diversity in B-cell function outside antibody production are just starting to be acknowledged and resolved. This series of reviews and papers that focus on human B cells will be divided across two issues. The first part of the review series in this issue captures practical information on identifying B-cell subtypes in blood in health and inflammatory diseases as well as describing aspects of B-cell diversity depending on immunoglobulin isotype and microanatomical context. It also explores our current understanding of cytokine production by human B cells and the effect of obesity on the B-cell response. The last review in this issue will reflect on the important lessons learned from the SARS-CoV-2 pandemic; in particular the role of antigen availability and its effect on B-cell memory and antibody production. [ABSTRACT FROM AUTHOR]

In this paper we review different aspects of B cell development on the path from the proB cell to the memory B cell and the plasmocyte. Emphasis is given to the positive and negative selection effects mediated by the changing forms of the surface immunoglobulin (Ig) receptor under successive microenvironments. Positive selection is linked to λ chain expression at the pro- and preB cell slage in fetal liver and bone marrow. Negative selection takes place when surface (s)IgM is being cross- linked by autoantigens before the immature B cell can leave, or after it has left, the bone marrow. After somatic mutation, major expansion becomes possible for B cells with high-affinity sIg receptors. This takes place in the germinal centres of the secondary lymphoid organs in the context of major histocompatibility complex (MHC) restriction and provided the necessary T cell help is given. Kinetic data on B cell replenishment in the rodent models are used to draw a schematic view of an established B cell repertoire. [ABSTRACT FROM AUTHOR]

The article presents various research papers related to complement deficiencies, published in an earlier issue of the journal "Clinical & Experimental Immunology". One of the abstracts talk about acquired deficiency in C1-inhibitor associated with an undifferentiated gastric adenocarcinoma. Acquired deficiency in C1-inhibitor (C1-INH) clinically manifests similar to hereditary angioedema and is usually associated with a B cell malignancy or is sometimes characterized by an autoantibody towards the C1-INH molecule.

The present paper describes two new MoAbs, GHI/75 and VMP55, which were raised against a glycoprotein enriched lysate of hairy cell leukaemia. These antibodies recognized a new antigen or 72 kD (unreduced) and 83 kD (reduced) molecular weight. GHI/75 and VMP55 gave very strong staining of plasma cells, moderate labelling of circulating B cells but only weak staining of monocytes., some tissue macrophages and lymphoid cells. Neither antibody reacted with neutrophils or any non-haematopoietic cells. Both antibodies, however, strongly labelled the tumour cells in hairy cell leukaemia, multiple mycloma, plasmacytoma and lymphoplasmacytic lymphomas. No staining was seen of the neoplaslic cells in Hodgkin's disease, myctoid leukaemia or T cell lymphomas. The two antibodies. GHI/75 and VMP55. may be of value in the differential diagnosis of hairy cell leukaemias and plasma cell neoplasms. In addition, the ease with which their antigen can be purified provides the possibility for a detailed study of this molecule. [ABSTRACT FROM AUTHOR]

Freshly isolated B cells from chronic lymphocytic leukaemia patients (B-CLL) have been previously shown to induce a strong proliferative response and high levels of NK-like activity in lymphocytes from healthy donors. The present paper deals with the origin, mitotic state, target spectrum and cell surface phenotype of the NK-like effectors generated after stimulation with B-CLL. Experiments using large granular lymphocytes (LGL) and T cells as responders demonstrated that most of the precursors of the newly generated NK-like effectors express the CD3 antigen. The induction of NK-like activity paralleled cell activation, as judged by blast transformation, thymidine uptake and appearance of cell surface activation markers. The newly generated NK-like effectors displayed a T cell phenotype and a broader target repertoire than native NK cells. [ABSTRACT FROM AUTHOR]

IL-2 receptor expression by B cells has previously been considered to be confined to activated normal B cells and, among the B cell leukaemias, to the hairy cells (HC) of hairy-cell leukaemia. In the present paper, using α-Tac monoclonal antibodies in a highly sensitive indirect rosette method, we show that both normal and certain leukaemic B cells other than HC express IL-2 receptors. The density of these receptors is low since they were not detectable by indirect immunofluorescence. Various controls excluded non-specific-reagent or exogenous receptor binding and blocking studies with recombinant IL-2 confirmed the presence of the IL-2 receptors. The significance of the findings is discussed and it is suggested that B cell IL-2 receptor expression without in-vitro activation may be a function of B cell maturity. [ABSTRACT FROM AUTHOR]

The initiation of cytoplasmic Ig synthesis in differentiating B cells is accompanied by the start of cytoplasmic J chain production. As the cell matures further. J chain synthesis ceases (unless it is producing dimeric IgA or 19S IgM). In consequence, it is common to find Ig-positive, J chain-negative cells in reactive lymphoid tissue. However, the reverse pattern (Ig-negative! J chain-positive), which would indicate J chain production unaccompanied by Ig synthesis, has not been reported. In this paper we describe the detection of such cells in reactive human lymphoid tissue by a double immunoenzymatic labelling technique. Furthermore, retrospective immunohistological analysis of 90 cases of human high-grade lymphoma revealed three cases in which the neoplastic cells appeared to synthesize J chain but not Ig. These findings suggest that the term J chain disease might be introduced to describe this new class of lymphoid neoplasm. However, it is pointed out that immunochemical categories of human B lymphoproliferative diseases based upon patterns of Ig synthesis are often in direct conflict with histological categories (cf. mu chain-producing neoplasms) and the term J chain disease cannot therefore be recommended. It is probable that further cases of J chain-positive, Ig-negative lymphoid neoplasms, covering a range of histological categories, will be described in the future. [ABSTRACT FROM AUTHOR]

Peripheral blood lymphocytes from 105 subjects with different forms of leprosy and healthy contacts of leprosy patients were stimulated in vitro with different preparations of mycobacterial antigens alone or in combination with a suboptimal dose of phytohaemagglutinin (PHA). In nearly all individuals sonicated leprosy bacilli and PHA together gave a lower 3H-thymidine incorporation than did the same dose of PHA alone. There was no difference in the degree of inhibition seen in the different patient groups or the healthy contacts. High doses of whole, washed Mycobacterium leprae, combined with PHA led to an increased thymidine incorporation in borderline tuberculoid leprosy patients who had experienced a reversal reaction, and in healthy contacts with more than 6 months of exposure, while most lepromatous patients and contacts with less than 6 months exposure did not show an augmentation of the PHA-induced thymidine incorporation. The inhibition exerted by sonicated M. leprae was dose-dependent, seen even with very low doses of antigen, and was not due to direct cytotoxicity. M. bovis, strain BCG, was weakly suppressive in combination with PHA, and sonicated M. duvalii had a very marked suppressive effect. There was no correlation between the suppressive effect of M. leprue antigens and the other mycobacteria neither was there any correlation with the responses to the mycobacterial antigens alone. Many lepromatous leprosy patients showed significant suppression of background incorporation with addition of M. leprae antigens. This paper discusses whether the apparent `non-responsiveness' in lepromatous leprosy could be due to active suppressor mechanisms operative in vivo. [ABSTRACT FROM AUTHOR]

In CD-1 mice infected with Trypanosoma musculi, the production of IgM and IgG antibodies in response to sheep erythrocytes (SRBC) was significantly suppressed when mice were immunized with SRBC once high parasitaemias had developed. In infected mice which were not immunized with SRBC, background plaque-forming responses of spleen cells to SRBC were significantly higher than in uninfected, unimmunized mice. Factors derived from T. musculi were found to be mitogenic m vitro for spleen cells taken from CD-1 mice. The mitogenic response to these factors by spleen cells from athymic mice was highly significant, whereas the response of spleen cells taken from CD-1 mice which had been pre-treated with cyclophosphamide was much less, suggesting that the B cell was the major target of the trypanosome-derived mitogen. In this paper we discuss the possible relationship of T. musculi-induced mitogenesis to the immunosuppression and non-specific antibody formation associated with T. musculi infections. [ABSTRACT FROM AUTHOR]

In previous in vitro studies the DNA synthesis in human blood lymphocytes induced by low concentration of PWM correlated with the percentage of hone marrow-derived (B) lymphocytes in cell suspensions. No correlation with lymphocyte subpopulations was noted when lymphocytes were activated by high concentrations of PWM. In this paper the hypothesis that low concentration of PWM mainly activates B lymphocytes was tested by measuring the (14C]thymidine incorporation into purified T or B lymphocytes from healthy donors. H lymphocytes were purified to 90-95°, by buoyant density centrifugation of T lymphocytes rosetted with sheep red blood cells. T lymphocytes were enriched by passage of lymphocytes through an IgG-anti-IgG-coated column. Low concentration of PWM-stimulated B lymphocytes but not T lymphocytes. while high concentrations of the stimulant activated both cell types. It was also noted that the B- hut not the T-lymphocyte fraction contained cells which synthesized DNA in the absence of PWM. [ABSTRACT FROM AUTHOR]

Mitogen-transformed human peripheral blood lymphocytes and tonsil blasts were examined by rosette formation to detect the presence of membrane-bound immunoglobulin (Ig) and surface receptors for fixed IgG and fixed C3. In addition, the capacity of these cells to rosette with sheep erythrocytes was evaluated as a reaction characteristic of T lymphocytes. In order for clear morphological recognition of the rosetting transformed lymphocytes and the rosetting tonsil blasts a cytocentrifuge technique was developed and used in conjunction with autoradiography and/or with Romanowsky stains. Using these techniques and the culture methods described in this paper phytohaemagglutinin, pokeweed mitogen, streptococcal filtrates and purified protein derivative stimulated predominantly T cells in the peripheral blood of man. A minority of the transformed cells in these mitogen-stimulated cultures (<24%) did rosette with B lymphocyte markers and presumably represent a B-cell response. No significant differences were found between the T- or B-cell specificity of the mitogens investigated. Lymphoid preparations from tonsils excised from normal donors with recurrent tonsillitis were found to contain 6-15% lymphoblasts and the iarge majority of these cells formed rosettes with the B-cell markers, less than 20% of these lymphoblasts formed spontaneous sheep erythrocyte rosettes. Using a mixed rosetting technique a small proportion (<5%) of PHA-transformed cells and tonsil lymphoblasts were found to have combined sheep Fc or combined sheep C3 receptors. The investigation of B- and T-lymphocyte surface markers on mitogentransformed lymphocytes was extended to neopiastic lymphocyte populations and it was found that the majority of transformed cells (>70%) present in chronic lymphocytic leukaemia cultures stimulated with PHA after 6 days incubation were transformed T lymphocytes. [ABSTRACT FROM AUTHOR]

Dysregulation of leukocyte trafficking, lipid metabolism, and other metabolic processes are the hallmarks that underpin and drive pathology in obesity. Current clinical management targets alternations in lifestyle choices (e.g. exercise, weight loss) to limit the impact of the disease. Crucially, re-gaining control over the pathogenic cellular and molecular processes may offer an alternative, complementary strategy for obese patients. Here we investigate the impact of the immunopeptide, PEPITEM, on pancreas homeostasis and leukocyte trafficking in mice on high-fed obesogenic diet (HFD). Both prophylactic and therapeutic treatment with PEPITEM alleviated the effects of HFD on the pancreas, reducing pancreatic beta cell size. Moreover, PEPITEM treatment also limited T-cell trafficking (CD4+ T-cells and KLRG1+ CD3+ T-cells) to obese visceral, but not subcutaneous, adipose tissue. Similarly, PEPITEM treatment reduced macrophage numbers within the peritoneal cavity of mice on HFD diet at both 6 and 12 weeks. By contrast, PEPITEM therapy elevated numbers of T and B cells were observed in the secondary lymphoid tissues (e.g. spleen and inguinal lymph node) when compared to the untreated HFD controls. Collectively our data highlights the potential for PEPITEM as a novel therapy to combat the systemic low-grade inflammation experienced in obesity and minimize the impact of obesity on pancreatic homeostasis. Thus, offering an alternative strategy to reduce the risk of developing obesity-related co-morbidities, such as type 2 diabetes mellitus, in individuals at high risk and struggling to control their weight through lifestyle modifications. In this manuscript, we demonstrate for the first time that therapeutic administration of the immunopeptide, PEPITEM, limits the pathological impact of obesity on the pancreas and systemic leukocyte trafficking, dampening the effects of obesity-induced systemic low-grade inflammation. Further work is required to determine the utility of PEPITEM as an alternative strategy to reduce the risk of developing obesity-related co-morbidities, such as type-2 diabetes, in individuals at high risk and struggling to control their weight through lifestyle modifications. [ABSTRACT FROM AUTHOR]

Summary: Obesity increases the risk of type 2 diabetes mellitus, cardiovascular disease, fatty liver disease, and cancer. It is also linked with more severe complications from infections, including COVID-19, and poor vaccine responses. Chronic, low-grade inflammation and associated immune perturbations play an important role in determining morbidity in people living with obesity. The contribution of B cells to immune dysregulation and meta-inflammation associated with obesity has been documented by studies over the past decade. With a focus on human studies, here we consolidate the observations demonstrating that there is altered B cell subset composition, differentiation, and function both systemically and in the adipose tissue of individuals living with obesity. Finally, we discuss the potential factors that drive B cell dysfunction in obesity and propose a model by which altered B cell subset composition in obesity underlies dysfunctional B cell responses to novel pathogens. Obesity—a major risk factor for multiple disorders, including cardiovascular disease and cancer—has tripled globally in less than 50 years and is associated with a chronic inflammatory response. B cells play a central role in driving obesity-associated meta-inflammation, and here we provide a consolidated summary of human B cell dysregulation and the molecular switches potentially driving this B cell dysregulation. A new frontier within the obesity research field, highlighted by the COVID-19 pandemic, is that obesity impacts the ability to respond to and clear infections and we propose a model by which obesity establishes a new "set-point" in the B cell compartment which contributes to this. [ABSTRACT FROM AUTHOR]

B cells are classically considered solely as antibody-producing cells driving humoral immune responses to foreign antigens in infections and vaccinations as well as self-antigens in pathological settings such as autoimmunity. However, it has now become clear that B cells can also secrete a vast array of cytokines, which influence both pro- and anti-inflammatory immune responses. Indeed, similarly to T cells, there is significant heterogeneity in cytokine-driven responses by B cells, ranging from the production of pro-inflammatory effector cytokines such as IL-6, through to the release of immunosuppressive cytokines such as IL-10. In this review, focusing on human B cells, we summarize the key findings that have revealed that cytokine-producing B cell subsets have critical functions in healthy immune responses and contribute to the pathophysiology of autoimmune diseases. B cells are classically considered solely as antibody-producing cells driving humoral immune responses to foreign antigens in infections and vaccinations as well as self-antigens in pathological settings such as autoimmunity. However, it has now become clear that B cells can also secrete a vast array of cytokines, which influence both pro- and anti-inflammatory immune responses. In this review, focusing on human B cells, we summarise the key findings that have revealed that cytokine-producing B cell subsets have critical functions in healthy immune responses and contribute to the pathophysiology of autoimmune diseases. [ABSTRACT FROM AUTHOR]

Summary: Most B cells in the human body are present in tissues where they support immune responses to pathogens, vaccines, autoantigens, and tumours. Despite their clear importance, they are very difficult to study and there are many areas of uncertainty that are difficult to resolve because of limited tissue access. In this review, we consider the zonal structure of lymphoid tissues, the B cell subsets they contain, and how these are regulated. We also discuss the impact that methods of deep interrogation have made on our current knowledge base, especially with respect to studies of cells from dissociated tissues. We discuss in some detail the controversial B cells with marginal zone distribution that some consider being archived memory B cells. We anticipate that more we understand of B cells in tissues and the niches they create, the more opportunities will be identified to harness their potential for therapeutic benefit. Here, Montorsi et al consider the zonal structure of human lymphoid tissues, the B cell subsets they contain, and how zonation is regulated. The impact of that methods of deep interrogation have made on our current knowledge base, especially with respect to studies of cells from dissociated tissues is discssed. The controversial issue of B cells with marginal zone distribution that some consider to be archived memory B cells is discussed. [ABSTRACT FROM AUTHOR]

Increased expression of substance P (SP) and neurokinin-1 receptor (NK1R) has been noticed in patients with allergic rhinitis (AR) and allergic asthma (AA). However, little is known of the expression of SP and NK1R in monocytes and B cells of AR and AA. In the present study, the expression levels of SP and NK1R were determined by flow cytometry and mouse AR and AA models. The results showed that both percentages of SP+ monocytes and SP+ B cells, and mean fluorescence intensity (MFI) of SP in monocytes were elevated in the blood of AA and AR combined with AA (ARA) patients. Similarly, the percentages of NK1R+ monocytes were elevated in the blood of AR, AA, and ARA patients. Allergens Artemisia sieversiana wild allergen extract (ASWE), house dust mite extract (HDME), and Platanus pollen allergen extract (PPE) increased the expression density of SP molecules (determined by MFI) in an individual monocyte of AR patients. HDME and PPE appeared to enhance SP and NK1R expression in the B cells of ARA and AR patients. In the mouse AR and AA models, the percentages of NK1R+ monocytes and B cells were elevated in blood following OVA (ovalbumin) sensitization and challenge. Knocking out the FcεRI molecule completely abolished the OVA-induced upregulation of expression of NK1R in monocytes and B cells of AA mice. In conclusion, upregulated expressions of SP and NK1R may contribute to the pathogenesis of airway allergy. Upregulated expressions of SP and NK1R in monocytes and B cells may play a role in the pathogenesis of AA, ARA and AR. Aerosol allergens can enhance SP and NK1R expressions in monocytes and B cells, which contribute to the development of these allergic airway disorders. A FcεRI associated mechanism may be involved in the OVA-induced upregulation of expression of NK1R in the monocytes and B cells of AA mice. [ABSTRACT FROM AUTHOR]

Although B cells are essential for humoral immunity and show noteworthy immunomodulatory activity through antibody-independent functions, the role of B cells in regulating Treg cell responses remains controversial. Tregs (CD4+CD25+Foxp3+) are considered to play an immunoprotective role in viral myocarditis (VMC) by controlling autoimmune effector T cells. Here, we proved that B-cell knockout can not only lead to significant reductions in Tregs in the spleen, blood, and heart of VMC mice but also decrease the activation and immune function of splenic Tregs, which was reversed by adoptive transfer of B cells; the transcription levels of TGF-β and Foxp3 in the myocardium were also significantly reduced. B-cell depletion by anti-CD20 impaired the anti-inflammatory function of splenic Tregs and the homeostasis of myocardial Tregs population. Moreover, B cells can convert CD4+CD25− T cells into Foxp3+ and Foxp3−, two functionally suppressive Treg subgroups. Although the reduction in myocardial inflammation in BKO mice indicates that B cells may play a proinflammatory role, the beneficial side of B cells cannot be ignored, that is, to control autoimmunity by maintaining Treg numbers. The results observed in the animal model of VMC highlight the potential harm of rituximab in the nonselective depletion of B cells in clinical applications. B cell depletion by anti-CD20 and gene knockout impaired the anti-inflammatory function of splenic Tregs and the homeostasis of myocardial Tregs population in the animal model of VMC. B cells could promote the transformation of Teffs into Foxp3+ and Foxp3-Tregs in vitro. [ABSTRACT FROM AUTHOR]

B cell dysfunction and inflammatory cytokine over‐production participate in the pathogenesis of rheumatoid arthritis (RA). Here we compared peripheral B cell homeostasis and immune functions between RA patients and healthy controls (HC) and explored vital signaling pathways involved in altered RA B cells. We found that RA patients showed significantly decreased frequencies of peripheral CD19+CD27+CD24high regulatory B (Breg) cells but increased frequencies of CD19+CD27+CD38high plasmablasts and CD19+CD138+ plasma cells, and higher levels of serum immunoglobulin (Ig)M and IgG. Compared to HC peripheral B cells, RA peripheral B cells had more increased proliferation and higher expression of activation markers. Importantly, our results showed that RA peripheral B cells displayed the mTOR signaling pathway to be more activated, and inhibition of mTOR could restore RA B cell homeostasis and functions. RA serum‐treated B cells exhibited more increased expressions of mTOR, which could be restored with the addition of anti‐interleukin (IL)‐27 neutralizing antibody. Serum IL‐27 levels were significantly increased in RA patients and positively correlated with disease activity, the frequencies of plasma cells and the levels of autoantibodies. In vitro, IL‐27 notably promoted immune dysfunction of RA B cells, which were inhibited by anti‐IL‐27 neutralizing antibody. Also, the mTOR pathway was more activated in IL‐27‐treated RA B cells, and mTOR inhibition apparently reversed abnormalities of RA B cells mediated by IL‐27. These results suggest that increased serum IL‐27 levels could promote peripheral B cell dysfunction in RA patients via activating the mTOR signaling pathway. Thus, IL‐27 may play a pro‐pathogenic role in the development of RA, and antagonizing IL‐27 could be a novel therapy strategy for RA. [ABSTRACT FROM AUTHOR]

Mucosa‐associated lymphoid tissue lymphoma‐translocation gene 1 (MALT1)‐deficiency is a rare combined immunodeficiency characterized by recurrent infections, dermatitis and enteropathy. We herein investigate the immunological profiles of our patient and previously reported children with MALT1‐deficiency. A mutation analysis was performed by targeted panel sequencing for primary immunodeficiency. Lymphocyte subset, activation and B cell differentiation were analyzed by flow cytometry and t‐distributed stochastic neighbor embedding. Pneumocystis pneumonia developed in a 6‐month‐old Japanese infant with atopic dermatitis, enteritis and growth restriction. This infant showed agammaglobulinemia without lymphopenia. At 8 years of age, the genetic diagnosis of MALT1‐deficiency was confirmed on a novel homozygous mutation of c.1102G>T, p.E368X. T cell stimulation tests showed impairments in the production of interleukin‐2, phosphorylation of nuclear factor kappa B (NF‐κB) p65 and differentiation of B cells. In combination with the literature data, we found that the number of circulatory B cells, but not T cells, were inversely correlated with the age of patients. The hematopoietic cell transplantation (HCT) successfully reconstituted the differentiation of mature B cells and T cells. These data conceptualize that patients with complete MALT1‐deficiency show aberrant differentiation and depletion of B cells. The early diagnosis and HCT lead to a cure of the disease phenotype associated with the loss‐of‐function mutations in human CARD11. [ABSTRACT FROM AUTHOR]

Summary: Human B cells could be divided into four classical subsets based on CD27 and immunoglobulin (Ig)D expression. Distinct from the other three well‐studied subsets, CD27−IgD− B cells, also termed as double‐negative (DN) B cells, have long been neglected. However, in recent years emerging evidence shows that DN B cells are unique memory B cells with important functions. They are expanded in a variety of diseases, especially in autoimmune diseases, contributing to the disease pathogenesis. Here, we briefly review the studies on DN B cells, including their origins, characteristics, subsets and roles in diseases, to try to bring new insights into this under‐recognized B cell subset. [ABSTRACT FROM AUTHOR]

A patient with intestinal lymphangiectasia (IL) was studied for his immunological abnormalities. The patient had hypoproteinaemia with severe hypogammaglobulinaemia. The results of lymphocyte subpopulation studies revealed a decrease of CD4+ cells and a decrease of surface immunoglobulin (sIg)-positive B lymphocytes. T cell functions determined by the proliferative responses against Concanavalin A (Con A) or phytohaemagglutinin (PHA) and by delayed type cutaneous hypersensitivity (DTH) response to purified protein derivatives (PPD) and PHA were normal. No immunoglobulin (Ig)-secreting cells were induced when his peripheral blood lymphocytes (PBL) were cultured with pokeweed mitogen (PWM). His T cells showed suppressor function to the PWM- induced differentiation of normal B cells. This suppressor activity was sensitive to 3000 rads irradiation. His B cells also failed to differentiate into Ig-producing cells with the help of normal T cells and PWM. Thus, in this patient, the decrease of Ig-synthesis in vitro could be attributed to suppressor T cells, lack of T helper cells and an intrinsic B cell defect. Therefore, this patient appears to have immunological abnormalities which differ from previously reported IL patients. [ABSTRACT FROM AUTHOR]

Four mouse monoclonal antibodies to human B cell surface determinants previously described as being directed against Ia like (MHC class II) antigens. have been shown to precipitate Ia α and β chains. Electrophoretic transfer experiments showed one antibody to be directed against Ia α chains and two others to be against Ia β chains. The antibodies were then used to analyse a range of cell types and a large number of lymphoblastoid and lymphoma cell lines. Ia antigens could not be detected on peripheral blood I cells, cord endothelium or T cell lines but their presence was confirmed on activated I cells and peripheral blood non-T cells. There was both qualitative and quantitative variation of Ia like antigen expression on B cell lines, including an apparent genetic polymorphism in α chain structure unrelated to DR allotypes and a single instance of a β chain of abnormally high molecular weight. [ABSTRACT FROM AUTHOR]

The development of the cell-mediated immune response (CMIR) to antigens prepared from Salmonella typhi was investigated in patients suffering from typhoid fever and in normal healthy subjects. The leucocyte migration inhibition test, blast transformation of lymphocytes and active rosette-forming cells were used for detecting CMIR. Peripheral blood lymphocytes were analysed for the numbers and proportions of B lymphocytes, T lymphocytes and their subpopulations with receptors for IgM (Tμ) or IgG (Tγ) and cells with Fc receptors for IgG. These parameters were correlated with the duration and the severity of illness. The uncomplicated cases of typhoid fever were found to have an intact CMIR as compared to the complicated cases. The ratio of T lymphocyte subpopulations was grossly imbalanced in typhoid patients, the numbers of T lymphocytes and their subpopulations were further altered in the complicated cases as compared to uncomplicated cases. The present study demonstrates a depressed state of CMIR in complicated patients with typhoid fever. CMIR may thus emerge as the cardinal point for recovery in typhoid fever rather than the specific antibodies. The study further demonstrates that imbalance within the subsets of T lymphocytes may be responsible for the depressed state of CMIR in complicated cases of typhoid fever. [ABSTRACT FROM AUTHOR]

T and B lymphocytes from blood and tonsils, as well as T and B lymphoid cell lines, phosphorylate deoxyguanosine which is probably the major toxic metabolite in purine nucleoside phosphorylase (PNP) deficiency. T and B cells also have similar activities of purine nucleoside phosphorylase. These findings indicate that the selective T cell defect in patients with PNP deficiency is unlikely to be due to a selective `trapping' of deoxyguanosine by T lymphocytes. [ABSTRACT FROM AUTHOR]

In eleven children with acute lymphocytic leukaemia (ALL), cytostatic treatment was stopped after sustained remission lasting for 9 months-6½ years. Their immunological status was monitored every 6-12 weeks during the first year after cessation of therapy. Rebound of depressed parameters was observed for absolute lymphocyte, B-cell and T-cell counts and for immunoglobulins. A simple follow-up scheme for such patients is proposed. [ABSTRACT FROM AUTHOR]

Summary: Systemic immune changes following ischaemic stroke are associated with increased susceptibility to infection and poor patient outcome due to their role in exacerbating the ischaemic injury and long‐term disability. Alterations to the abundance or function of almost all components of the immune system post‐stroke have been identified, including lymphocytes, monocytes and granulocytes. However, subsequent infections have often confounded the identification of stroke‐specific effects. Global understanding of very early changes to systemic immunity is critical to identify immune targets to improve clinical outcome. To this end, we performed a small, prospective, observational study in stroke patients with immunophenotyping at a hyperacute time point (< 3 h) to explore early changes to circulating immune cells. We report, for the first time, decreased frequencies of type 1 conventional dendritic cells (cDC1), haematopoietic stem and progenitor cells (HSPCs), unswitched memory B cells and terminally differentiated effector memory T cells re‐expressing CD45RA (TEMRA). We also observed concomitant alterations to human leucocyte antigen D‐related (HLA‐DR), CD64 and CD14 expression in distinct myeloid subsets and a rapid activation of CD4+ T cells based on CD69 expression. The CD69+CD4+ T cell phenotype inversely correlated with stroke severity and was associated with naive and central memory T (TCM) cells. Our findings highlight early changes in both the innate and adaptive immune compartments for further investigation as they could have implications the development of post‐stroke infection and poorer patient outcomes. [ABSTRACT FROM AUTHOR]

Summary: Myasthenia gravis (MG) is characterized by muscle weakness and fatigue caused by the presence of autoantibodies against the acetylcholine receptor (AChR) or the muscle‐specific tyrosine kinase (MuSK). Activated T, B and plasma cells, as well as cytokines, play important roles in the production of pathogenic autoantibodies and the induction of inflammation at the neuromuscular junction in MG. Many studies have focused on the role of cytokines and lymphocytes in anti‐AChR antibody‐positive MG. Chronic inflammation mediated by T helper type 17 (Th17) cells, the promotion of autoantibody production from B cells and plasma cells by follicular Th (Tfh) cells and the activation of the immune response by dysfunction of regulatory T (Treg) cells may contribute to the exacerbation of the MG pathogenesis. In fact, an increased number of Th17 cells and Tfh cells and dysfunction of Treg cells have been reported in patients with anti‐AChR antibody‐positive MG; moreover, the number of these cells was correlated with clinical parameters in patients with MG. Regarding cytokines, interleukin (IL)‐17; a Th17‐related cytokine, IL‐21 (a Tfh‐related cytokine), the B‐cell‐activating factor (BAFF; a B cell‐related cytokine) and a proliferation‐inducing ligand (APRIL; a B cell‐related cytokine) have been reported to be up‐regulated and associated with clinical parameters of MG. This review focuses on the current understanding of the involvement of cytokines and lymphocytes in the immunological pathogenesis of MG, which may lead to the development of novel therapies for this disease in the near future. [ABSTRACT FROM AUTHOR]

Summary: Autoimmune rheumatic diseases (AIRD) are categorized seropositive or seronegative, dependent upon the presence or absence of specific autoreactive antibodies, including rheumatoid factor and anti‐citrullinated protein antibodies. Autoantibody‐based diagnostics have proved helpful in patient care, not only for diagnosis but also for monitoring of disease activity and prediction of therapy responsiveness. Recent work demonstrates that AIRD patients develop autoantibodies beyond those contained in the original categorization. In this study we discuss key mechanisms that underlie autoantibody development in AIRD: defects in early B cell development, genetic variants involved in regulating B cell and T cell tolerance, environmental triggers and antigen modification. We describe how autoantibodies can directly contribute to AIRD pathogenesis through innate and adaptive immune mechanisms, eventually culminating in systemic inflammation and localized tissue damage. We conclude by discussing recent insights that suggest distinct AIRD have incorrectly been denominated seronegative. [ABSTRACT FROM AUTHOR]

Summary: Systemic sclerosis (SSc) is a T helper type 2 (Th2)‐associated autoimmune disease characterized by vasculopathy and fibrosis. Efficacy of B cell depletion therapy underscores antibody‐independent functions of B cells in SSc. A recent study showed that the Th2 cytokine interleukin (IL)‐4 induces granulocyte–macrophage colony‐stimulating factor (GM‐CSF)‐producing effector B cells (GM‐Beffs) in humans. In this study, we sought to elucidate the generation mechanism of GM‐Beffs and also determine a role of this subset in SSc. Among Th‐associated cytokines, IL‐4 most significantly facilitated the generation of GM‐Beffs within memory B cells in healthy controls (HCs). In addition, the profibrotic cytokine transforming growth factor (TGF)‐β further potentiated IL‐4‐ and IL‐13‐induced GM‐Beffs. Of note, tofacitinib, a Janus kinase (JAK) inhibitor, inhibited the expression of GM‐CSF mRNA and protein in memory B cells induced by IL‐4, but not by TGF‐β. GM‐Beffs were enriched within CD20+CD30+CD38−/low cells, a distinct population from plasmablasts, suggesting that GM‐Beffs exert antibody‐independent functions. GM‐Beffs were also enriched in a CD30+ fraction of freshly isolated B cells. GM‐Beffs generated under Th2 conditions facilitated the differentiation from CD14+ monocytes to DC‐SIGN+CD1a+CD14−CD86+ cells, which significantly promoted the proliferation of naive T cells. CD30+ GM‐Beffs were more pronounced in patients with SSc than in HCs. A subpopulation of SSc patients with the diffuse type and concomitant interstitial lung disease exhibited high numbers of GM‐Beffs. Together, these findings suggest that human GM‐Beffs are enriched in a CD30+ B cell subset and play a role in the pathogenesis of SSc. [ABSTRACT FROM AUTHOR]

Summary: Systemic lupus erythematosus is a chronic inflammatory disease which involves multiple organs. Self‐specific B and T cells play a main role in the pathogenesis of lupus and have been defined as a logical target for selective therapy. The protein annexin A1 (ANX A1) is a modulator of the immune system involving many cell types. An abnormal expression of ANX A1 was found on activated B and T cells during autoimmunity, suggesting its importance as a potential therapeutic target. We hypothesize that it may be possible to down‐regulate the activity of autoreactive T and B cells from lupus patients in a humanized immunodeficient mouse model by treating them with an antibody against ANX A1. When cultured in the presence of anti‐ANX A1, peripheral blood mononuclear cells (PBMC) from lupus patients showed a decreased number of immunoglobulin (Ig)G anti‐dsDNA antibody‐secreting plasma cells, decreased T cell proliferation and expression of activation markers and increased B and T cell apoptosis. We employed a humanized model of SLE by transferring PBMCs from lupus patients to immunodeficient non‐obese diabetic‐severe combined immunodeficient (NOD‐SCID) mice. The humanized animals presented autoantibodies, proteinuria and immunoglobulin deposition in the renal glomeruli. Treatment of these NOD‐SCID mice with an anti‐ANX A1 antibody prevented appearance of anti‐DNA antibodies and proteinuria, while the phosphate‐buffered saline (PBS)‐injected animals had high levels after the transfer. The treatment reduced the levels of autoantibodies to several autoantigens, lupus‐associated cytokines and disease symptoms. [ABSTRACT FROM AUTHOR]

Summary: Various reports of disease‐related lung pathologies in common variable immunodeficiency disorder (CVID) patients have been published, with differing histological and high‐resolution computed tomography (HRCT) findings. Data were extracted from the validated Oxford Primary Immune Deficiencies  Database (PID) database (1986–2016) on adult, sporadic CVID patients with suspected interstitial lung disease (ILD). Histology of lung biopsies was studied in relation to length of follow‐up, clinical outcomes, HRCT findings and chest symptoms, to look for evidence for different pathological processes. Twenty‐nine CVID patients with lung histology and/or radiological evidence of ILD were followed. After exclusions, lung biopsies from 16 patients were reanalysed for ILD. There were no well‐formed granulomata, even though 10 patients had systemic, biopsy‐proven granulomata in other organs. Lymphocytic infiltration without recognizable histological pattern was the most common finding, usually with another feature. On immunochemistry (n = 5), lymphocytic infiltration was due to T cells (CD4 or CD8). Only one patient showed B cell follicles with germinal centres. Interstitial inflammation was common; only four of 11 such biopsies also showed interstitial fibrosis. Outcomes were variable and not related to histology, suggesting possible different pathologies. The frequent nodules on HRCT were not correlated with histology, as there were no well‐formed granulomata. Five patients were asymptomatic, so it is essential for all patients to undergo HRCT, and to biopsy if abnormal HRCT findings are seen. Internationally standardized pathology and immunochemical data are needed for longitudinal studies to determine the precise pathologies and prognoses in this severe complication of CVIDs, so that appropriate therapies may be found. [ABSTRACT FROM AUTHOR]

Summary: Type 1 diabetes mellitus is an autoimmune metabolic disorder characterized by chronic hyperglycemia, the presence of autoreactive T and B cells and autoantibodies against self‐antigens. A membrane‐bound enzyme on the pancreatic beta‐cells, glutamic acid decarboxylase 65 (GAD65), is one of the main autoantigens in type 1 diabetes. Autoantibodies against GAD65 are potentially involved in beta‐cell destruction and decline of pancreatic functions. The human complement receptor type 1 (CD35) on B and T lymphocytes has a suppressive activity on these cells. We hypothesized that it may be possible to eliminate GAD65‐specific B cells from type 1 diabetes patients by using chimeric molecules, containing an anti‐CD35 antibody, coupled to peptides resembling GAD65 B/T epitopes. These molecules are expected to selectively bind the anti‐GAD65 specific B cells by the co‐cross‐linking of the immunoglobulin receptor and CD35 and to deliver a suppressive signal. Two synthetic peptides derived from GAD65 protein (GAD65 epitopes) and anti‐CD35 monoclonal antibody were used for the construction of two chimeras. The immunomodulatory activity of the engineered antibodies was tested in vitro using peripheral blood mononuclear cells (PBMCs) from type 1 diabetes patients. A reduction in the number of anti‐GAD65 IgG antibody‐secreting plasma cells and increased percentage of apoptotic B lymphocytes was observed after treatment of these PBMCs with the engineered antibodies. The constructed chimeric molecules are able to selectively modulate the activity of GAD65‐specific B lymphocytes and the production of anti‐GAD65 IgG autoantibodies by co‐cross‐linking of the inhibitory CD35 and the B cell antigen receptor (BCR). This treatment presents a possible way to alter the autoimmune nature of these cells. [ABSTRACT FROM AUTHOR]

Summary: There is currently scarce knowledge of the immunological profile of patients with latent autoimmune diabetes mellitus in the adult (LADA) when compared with healthy controls (HC) and patients with classical type 1 diabetes (T1D) and type 2 diabetes (T2D). The objective of this study was to investigate the cellular immunological profile of LADA patients and compare to HC and patients with T1D and T2D. All patients and age‐matched HC were recruited from Uppsala County. Peripheral blood mononuclear cells were isolated from freshly collected blood to determine the proportions of immune cells by flow cytometry. Plasma concentrations of the cytokine interleukin (IL)‐35 were measured by enzyme‐linked immunosorbent assay (ELISA). The proportion of CD11c+CD123– antigen‐presenting cells (APCs) was lower, while the proportions of CD11c+CD123+ APCs and IL‐35+ tolerogenic APCs were higher in LADA patients than in T1D patients. The proportion of CD3–CD56highCD16+ natural killer (NK) cells was higher in LADA patients than in both HC and T2D patients. The frequency of IL‐35+ regulatory T cells and plasma IL‐35 concentrations in LADA patients were similar to those in T1D and T2D patients, but lower than in HC. The proportion of regulatory B cells in LADA patients was higher than in healthy controls, T1D and T2D patients, and the frequency of IL‐35+ regulatory B cells was higher than in T1D patients. LADA presents a mixed cellular immunological pattern with features overlapping with both T1D and T2D. [ABSTRACT FROM AUTHOR]

Summary: Systemic sclerosis (SSc) is an idiopathic systemic autoimmune disease. It is characterized by a triad of hallmarks: immune dysfunction, fibrosis and vasculopathy. Immune dysfunction in SSc is characterized by the activation and recruitment of immune cells and the production of autoantibodies and cytokines. How immune abnormalities link the fibrosis and vasculopathy in SSc is poorly understood. A plethora of immune cell types are implicated in the immunopathogenesis of SSc, including T cells, B cells, dendritic cells, mast cells and macrophages. How these different cell types interact to contribute to SSc is complicated, and can involve cell‐to‐cell interactions and communication via cytokines, including transforming growth factor (TGF)‐β, interleukin (IL)‐6 and IL‐4. We will attempt to review significant and recent research demonstrating the importance of immune cell regulation in the immunopathogenesis of SSc with a particular focus on fibrosis. We investigate the immunological basis of systemic sclerosis in this review article. Evidence points to a key role of both the innate and the adaptive immune system in driving the pathology. Drugs targeting these pathways could be novel therapeutics in systemic sclerosis. [ABSTRACT FROM AUTHOR]

Summary: The objective of this study was to test the capacity of a newly developed fusion protein of interleukin 4 (IL‐4) and IL‐10 [IL4‐10 fusion protein (FP)] to shift multiple pro‐inflammatory pathways towards immune regulation, and to inhibit pro‐inflammatory activity in arthritis models. The effects of IL4‐10 FP in comparison with IL‐4, IL‐10 and IL‐4 plus IL‐10 on pro‐ and anti‐inflammatory mediators, T cells and immunoglobulin (Ig) receptors in favour of immunoregulatory activity were studied. In addition, the capacity of IL4‐10 FP to inhibit pro‐inflammatory activity in ex‐vivo and in‐vivo arthritis models was investigated. IL4‐10 FP robustly inhibited pro‐inflammatory cytokine [IL‐1β, tumour necrosis factor (TNF)‐α, IL‐6 and IL‐8] production in whole blood cultures, mediated by both the IL‐10 and the IL‐4 moiety. IL4‐10 fusion protein induced IL‐1 receptor antagonist (IL‐1RA) production and preserved soluble TNF receptor (sTNFR) levels, strongly increasing IL‐1RA/IL‐1β and sTNFR/TNF‐α ratios. In addition, IL4‐10 FP strongly inhibited T helper (Th) type 1 and 17 cytokine secretion, while maintaining FoxP3 expression and up‐regulating Th2 activity. In addition, while largely leaving expression of activating Fc gamma receptor (FcγR)I, III and Fc epsilon receptor (FcεR) unaffected, it significantly shifted the FcγRIIa/FcγRIIb ratio in favour of the inhibitory FcγRIIb. Moreover, IL4–10 FP robustly inhibited secretion of pro‐inflammatory cytokines by rheumatoid arthritis synovial tissue and suppressed experimental arthritis in mice, without inducing B cell hyperactivity. IL4‐10 fusion protein is a novel drug, signalling cells to induce immunoregulatory activity that overcomes limitations of IL‐4 and IL‐10 stand‐alone therapy, and therefore has therapeutic potential for inflammatory diseases such as rheumatoid arthritis. IL4‐10 fusion protein (IL4–10 FP) combines two potent anti‐inflammatory cytokines with unique properties into one molecule. IL4‐10 FP signals cells to induce robust immunoregulatory activity, strongly inhibiting pro‐inflammatory cytokine production by RA synovial tissue explants and suppressing experimental arthritis in mice. IL4‐10 fusion protein overcomes limitations of IL‐4 and IL‐10 stand‐alone therapy and therefore has therapeutic potential for the treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Summary: Alemtuzumab, a humanized anti‐CD52 monoclonal antibody, is approved for treatment of relapsing multiple sclerosis (MS). In the Phase II/III trials, patients received 12 or 24 mg/day of alemtuzumab in two treatment courses (5 days for course 1 and 3 days for course 2), 12 months apart. Serum concentrations of alemtuzumab peaked on the last day of dosing in each course and mostly fell below the limit of quantitation by day 30. Alemtuzumab rapidly depleted circulating T and B lymphocytes, with the lowest observed values occurring within days. Lymphocytes repopulated over time, with B cell recovery usually complete within 6 months. T lymphocytes recovered more slowly and generally did not return to baseline by 12 months post‐treatment. Approximately 40 and 80% of patients had total lymphocyte counts, reaching the lower limit of normal by 6 and 12 months after each course, respectively. The clearance of alemtuzumab is dependent on circulating lymphocyte count. A majority of treated patients tested positive for anti‐alemtuzumab antibodies, including inhibitory antibodies, during the 2‐year studies, and a higher proportion of patients tested positive in course 2 than in course 1. The presence of anti‐alemtuzumab antibody appeared to be associated with slower clearance of alemtuzumab from the circulation but had no impact on the pharmacodynamics. No effects of age, race or gender on the pharmacokinetics or pharmacodynamics were observed. Together, the pharmacokinetics, pharmacodynamics and immunogenicity results support the continued development and use of alemtuzumab for the treatment of MS, and probably explain its sustained effects beyond the dosing interval. Alemtuzumab, a humanized anti‐CD52 monoclonal antibody, given to multiple sclerosis (MS) patients at 12 or 24 mg/day in two treatment courses (5 days for course 1 and 3 days for course 2), 12 months apart, rapidly depleted circulating T and B lymphocytes, with the lowest observed values occurring within days. Lymphocytes repopulated over time, with B cell recovery usually complete within 6 months. T lymphocytes recovered more slowly and generally did not return to baseline by 12 months post‐treatment. The pharmacokinetics, pharmacodynamics and immunogenicity of alemtuzumab in MS were discussed. [ABSTRACT FROM AUTHOR]

Summary: We hypothesize that T cells such as interleukin (IL)‐21+B cell lymphoma 6 (BCL6)+ T follicular helper cells can regulate B cell‐mediated immunity within the allograft during acute T cell‐mediated rejection; this process may feed chronic allograft rejection in the long term. To investigate this mechanism, we determined the presence and activation status of organized T and B cells in so‐called ectopic lymphoid structures (ELSs) in different types of acute renal allograft rejection. Biopsies showing the following primary diagnosis were included: acute/active antibody‐mediated rejection, C4d+ (a/aABMR), acute T cell‐mediated rejection grade I (aTCMRI) and acute T cell‐mediated rejection grade II (aTCMRII). Paraffin sections were stained for T cells (CD3 and CD4), B cells (CD20), follicular dendritic cells (FDCs, CD23), activated B cells (CD79A), immunoglobulin (Ig)D, cell proliferation (Ki67) and double immunofluorescent stainings for IL‐21 and BCL6 were performed. Infiltrates of T cells were detected in all biopsies. In aTCMRI, B cells formed aggregates surrounded by T cells. In these aggregates, FDCs, IgD and Ki67 were detected, suggesting the presence of ELSs. In contrast, a/aABMR and aTCMRII showed diffuse infiltrates of T and B cells but no FDCs and IgD. IL‐21 was present in all biopsies. However, co‐localization with BCL6 was observed mainly in aTCMRI biopsies. In conclusion, ELSs with an activated phenotype are found predominantly in aTCMRI where T cells co‐localize with B cells. These findings suggest a direct pathway of B cell alloactivation at the graft site during T cell mediated rejection. [ABSTRACT FROM AUTHOR]

Summary: Defining how self‐antigens are perceived by the immune system is pivotal to understand how tolerance is maintained under homeostatic conditions. Clinically relevant, natural autoantigens targeted by autoantibodies, in e.g. systemic lupus erythematosus (SLE), commonly have an intrinsic ability to engage not only the B cell receptor (BCR), but also a co‐stimulatory pathway in B cells, such as the Toll‐like receptor (TLR)‐7 pathway. Here we developed a novel mouse model displaying inducible expression of a fluorescent epidermal neo‐autoantigen carrying an OT‐II T cell epitope, B cell antigen and associated ribonucleic acids capable of stimulating TLR‐7. The neo‐autoantigen was expressed in skin, but did not drain in intact form into draining lymph nodes, even after ultraviolet B (UVB)‐stimulated induction of apoptosis in the basal layer. Adoptively transferred autoreactive B cells were excluded follicularly and perished at the T–B border in the spleen, preventing their recirculation and encounter with antigen peripherally. This transitional check‐point was bypassed by crossing the reporter to a BCR knock‐in line on a C4‐deficient background. Adoptively transferred OT‐II T cells homed rapidly into cutaneous lymph nodes and up‐regulated CD69. Surprisingly, however, tolerance was not broken, as the T cells subsequently down‐regulated activation markers and contracted. Our results highlight how sequestration of intracellular and peripheral antigen, the transitional B cell tolerance check‐point and T cell regulation co‐operate to maintain immunological tolerance in vivo. [ABSTRACT FROM AUTHOR]

We have demonstrated previously that histone deacetylase (HDAC6) expression is increased in animal models of systemic lupus erythematosus (SLE) and that inhibition of HDAC6 decreased disease. In our current studies, we tested if an orally active selective HDAC6 inhibitor would decrease disease pathogenesis in a lupus mouse model with established early disease. Additionally, we sought to delineate the cellular and molecular mechanism(s) of action of a selective HDAC6 inhibitor in SLE. We treated 20-week-old (early-disease) New Zealand Black (NZB)/White F1 female mice with two different doses of the selective HDAC6 inhibitor (ACY-738) for 5 weeks. As the mice aged, we determined autoantibody production and cytokine levels by enzyme-linked immunosorbent assay (ELISA) and renal function by measuring proteinuria. At the termination of the study, we performed a comprehensive analysis on B cells, T cells and innate immune cells using flow cytometry and examined renal tissue for immune-mediated pathogenesis using immunohistochemistry and immunofluorescence. Our results showed a reduced germinal centre B cell response, decreased T follicular helper cells and diminished interferon (IFN)-γ production from T helper cells in splenic tissue. Additionally, we found the IFN-α-producing ability of plasmacytoid dendritic cells was decreased along with immunoglobulin isotype switching and the generation of pathogenic autoantibodies. Renal tissue showed decreased immunoglobulin deposition and reduced inflammation as judged by glomerular and interstitial inflammation. Taken together, these studies show selective HDAC6 inhibition decreased several parameters of disease pathogenesis in lupus-prone mice. The decrease was due in part to inhibition of B cell development and response. [ABSTRACT FROM AUTHOR]

Ras-associated lymphoproliferative disease (RALD) is an autoimmune lymphoproliferative syndrome (ALPS)-like disease caused by mutations in Kirsten rat sarcoma viral oncogene homologue ( KRAS) or neuroblastoma RAS viral (V-Ras) oncogene homologue ( NRAS). The immunological phenotype and pathogenesis of RALD have yet to be studied extensively. Here we report a thorough immunological investigation of a RALD patient with a somatic KRAS mutation. Patient lymphocytes were analysed for phenotype, immunoglobulin levels and T cell proliferation capacity. T and B cell receptor excision circles (TREC and KREC, respectively), markers of naive T and B cell production, were measured serially for 3 years. T and B cell receptor repertoires were studied using both traditional assays as well as next-generation sequencing (NGS). TREC and KREC declined dramatically with time, as did T cell receptor diversity. NGS analysis demonstrated T and B clonal expansions and marked restriction of T and B cell receptor repertoires compared to healthy controls. Our results demonstrate, at least for our reported RALD patient, how peripheral T and B clonal expansions reciprocally limit lymphocyte production and restrict the lymphocyte receptor repertoire in this disease. Decreased naive lymphocyte production correlated with a clinical deterioration in our patient's immune status, suggesting that TREC and KREC may be used as an aid in monitoring disease progression. Both the methodologies used here and the conclusions regarding immune homeostasis may be applicable to the research of ALPS and other immune dysregulation syndromes. [ABSTRACT FROM AUTHOR]

The current view of type 1 diabetes (T1D) is that it is an immune-mediated disease where lymphocytes infiltrate the pancreatic islets, promote killing of beta cells and cause overt diabetes. Although tissue resident immune cells have been demonstrated in several organs, the composition of lymphocytes in human healthy pancreatic islets have been scarcely studied. Here we aimed to investigate the phenotype of immune cells associated with human islets of non-diabetic organ donors. A flow cytometry analysis of isolated islets from perfused pancreases ( n = 38) was employed to identify alpha, beta, T, natural killer (NK) and B cells. Moreover, the expression of insulin and glucagon transcripts was evaluated by RNA sequencing. Up to 80% of the lymphocytes were CD3+ T cells with a remarkable bias towards CD8+ cells. Central memory and effector memory phenotypes dominated within the CD8+ and CD4+ T cells and most CD8+ T cells were positive for CD69 and up to 50-70% for CD103, both markers of resident memory cells. The frequency of B and NK cells was low in most islet preparations (12 and 3% of CD45+ cells, respectively), and the frequency of alpha and beta cells varied between donors and correlated clearly with insulin and glucagon mRNA expression. In conclusion, we demonstrated the predominance of canonical tissue resident memory CD8+ T cells associated with human islets. We believe that these results are important to understand more clearly the immunobiology of human islets and the disease-related phenotypes observed in diabetes. [ABSTRACT FROM AUTHOR]

B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) help in B cell activation, maintenance and plasma cell survival. B cell infiltration has been demonstrated in kidneys of patients with lupus nephritis (LN). Serum levels of BAFF and APRIL have shown inconsistent relationships with lupus disease activity. We evaluated urinary levels of BAFF and APRIL as biomarker for LN. Thirty-six patients with proliferative lupus nephritis (AN), 10 with active lupus without nephritis (AL) and 15 healthy controls (HC) were studied. APRIL and BAFF levels were measured in both serum and urine using enzyme-linked immunosorbent assay (ELISA). Urine levels were normalized for urinary creatinine excretion. Urine levels were correlated with conventional disease activity markers and histology. Levels were reassessed in 20 AN patients at 6 months after treatment with cyclophosphamide. Urinary APRIL (uAPRIL) and BAFF (uBAFF) levels were raised significantly in AN. uAPRIL, but not uBAFF, correlated moderately with renal Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) in AN ( r = 0·36, P < 0·05). On receiver operator curve (ROC) analysis, uBAFF and uAPRIL showed an area under the curve (AUC) of 0·825 and 0·781, respectively, in differentiating between nephritis and non-nephritis, which performed better than low C3, C4 and raised anti-dsDNA antibodies. There was no correlation of serum levels with uBAFF ( r = 0·187, P = 0·261) and uAPRIL ( r = 0·114, P = 0·494). uAPRIL levels reduced after treatment (mean 125 pg/mg to 36 pg/mg, P < 0·05). uBAFF levels reduced in 16 responders while two of four non-responders had increase in levels. Thus, uBAFF and uAPRIL are potential biomarkers of proliferative lupus nephritis. [ABSTRACT FROM AUTHOR]

Ageing is characterized by increased low-grade chronic inflammation, which is a significant risk factor for morbidity and mortality of elderly individuals. Similar to ageing, obesity is considered to be an inflammatory predisposition associated with chronic activation of immune cells and consequent local and systemic inflammation. Both ageing and obesity are characterized by reduced innate and adaptive immune responses. This review focuses on B cells, how they may contribute, at least locally, to low-grade chronic inflammation in ageing and obesity and on the mechanisms involved. [ABSTRACT FROM AUTHOR]

The complement receptor 2 (CR2, CD21) is part of a complex (CD21/CD19/CD81) acting as a co-receptor to the B cell receptor (BCR). Simultaneous triggering of the BCR and CD21 lowers the threshold for B cell activation. Although CD21 is important, B cells that express low amounts or lack surface CD21 (CD21-/low) are increased in conditions with chronic inflammation, e.g. autoimmune diseases. However, little is known about the CD21-/low B cell subset in peripheral blood from healthy donors. Here, we show that CD21-/low cells represent approximately 5% of B cells in peripheral blood from adults but are barely detectable in cord blood, after excluding transitional B cells. The CD21-/low subset can be divided into CD38-24+ and CD38-24low cells, where most of the CD38-24+ are CD27+immunoglobulin (Ig)M+IgD+ and the CD38-24low are switched CD27-. Expression levels of additional markers, e.g. CD95 and CD62L, are similar to those on classical memory B cells. In contrast to naive cells, the majority of CD21-/low cells lack expression of the ABCB1 transporter. Stimulation with a combination of BCR, Toll-like receptor (TLR)−7/8 and interleukin (IL)−2 induces proliferation and differentiation of the CD21-/low B cells comparable to CD21+CD27+ memory B cells. The response excluding BCR agonist is not on par with that of classical memory B cells, although clearly above that of naive B cells. This is ascribed to a weaker response by the CD38-24low subset, implying that some memory B cells require not only TLR but also BCR triggering. We conclude that the CD21-/low cells in healthy donors are memory B cells. [ABSTRACT FROM AUTHOR]

The recruitment of immune cells to sites of tissue inflammation is orchestrated by chemokine/chemokine receptor networks. Among these, the CXCL13/CXCR5 axis is thought to be involved critically in systemic lupus erythematosus (SLE) and lupus nephritis pathogenesis. Beyond B cell abnormalities, another hallmark of SLE disease is the occurrence of aberrant T cell responses. In particular, double-negative (DN) T cells are expanded in the peripheral blood of patients with SLE and in lupus-prone mice. DN T cells induce immunoglobulin production, secrete proinflammatory cytokines and infiltrate inflamed tissue, including kidneys. We aimed to investigate how CXCR5 deficiency changes immune cell trafficking in murine lupus. We therefore crossed CXCR5-/- mice with B6/lpr mice, a well-established murine lupus model. B cell numbers and B cellular immune responses were diminished in CXCR5-deficient B6/lpr mice. In addition, we observed reduced accumulation of DN T cells in spleen and lymph nodes, paralleled by reduced splenomegaly and lymphadenopathy. In-vivo migration assays revealed reduced migration of CXCR5-deficient DN T cells into lymph nodes, and ex-vivo-activated CXCR5-deficient DN T cells failed to infiltrate kidneys of recipients. Moreover, DN T cells and B cells of CXCR5-deficient B6/lpr mice failed to migrate towards CXCL13 in vitro. We propose that CXCR5 is involved critically in B cell trafficking and germinal cell (GC) formation in murine lupus and in guiding pathogenic DN T cells into lymphoid organs and kidneys, and we therefore describe new pathomechanisms for the CXCL13/CXCR5 axis in SLE. [ABSTRACT FROM AUTHOR]

B7-2-/- non-obese diabetic (NOD) mice develop a spontaneous autoimmune polyneuropathy (SAP) that mimics the progressive form of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). In this study, we focused on the role of regulatory T cells (Tregs) and regulatory B cells (Bregs) in SAP. We found that deletion of B7-2 in female NOD mice led to a lower frequency and number of Tregs and Bregs in spleens and lymph nodes. Tregs but not Bregs suppressed antigen-stimulated splenocyte proliferation, whereas Bregs inhibited the T helper type 1 (Th1) cytokine response. Both Tregs and Bregs induced an increase in CD4+interleukin (IL)−10+ cells, although less effectively in the absence of B7-2. Adoptive transfer studies revealed that Tregs, but not Bregs, suppressed SAP, while Bregs attenuated disease severity when given prior to symptom onset. B cell deficiency in B cell-deficient (muMT)/B7-2-/- NOD mice prevented the development of SAP, which would indicate that the pathogenic role of B cells predominates over its regulatory role in this model. We conclude that Bregs and Tregs control the immunopathogenesis and progression of SAP in a non-redundant fashion, and that therapies aimed at expansion of Bregs and Tregs may be an effective approach in autoimmune neuropathies. [ABSTRACT FROM AUTHOR]

The gene PIK3CD codes for the catalytic subunit of phosphoinositide 3-kinase δ (PI3K δ), and is expressed solely in leucocytes. Activating mutations of PIK3CD have been described to cause an autosomal dominant immunodeficiency that shares clinical features with common variable immunodeficiency (CVID). We screened a cohort of 669 molecularly undefined primary immunodeficiency patients for five reported mutations (four gain-of-function mutations in PIK3CD and a loss of function mutation in PIK3R1) using pyrosequencing. PIK3CD mutations were identified in three siblings diagnosed with CVID and two sporadic cases with a combined immunodeficiency (CID). The PIK3R1 mutation was not identified in the cohort. Our patients with activated PI3Kδ syndrome (APDS) showed a range of clinical and immunological findings, even within a single family, but shared a reduction in naive T cells. PIK3CD gain of function mutations are more likely to occur in patients with defective B and T cell responses and should be screened for in CVID and CID, but are less likely in patients with a pure B cell/hypogammaglobulinaemia phenotype. [ABSTRACT FROM AUTHOR]