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

Lists research papers related to immunology to be published in the journal. "T Cells Homeostasis in Mice Exposed to Airborne Xenobiotics," by Nadzieja Drela, Justyna Bien, and Ewa Kozlowska; "B Cell Reconstruction by Transplantation of B220+ CD117+ B-lymphoid Progenitors Into Irradiated Mice," by Susumu Kawaguchi; "TGF-β1 Increases CXCR4 Expression, SDF-1alpha-stimulated Signaling and HIV-1 Entry in Human Monocyte-derived Macrophages," by Jeffrey Harrison.

The article presents a list of forthcoming books about immunology. These include "IL-5 Target Genes Involved in B Cell Terminal Maturation," by Keisuke Horikawa and K. Takatsu, "The Riddle of the Dual Expression of IgM and IgD," by Roland Geisberger, Marinus Lamers and Gernot Achatz, and "Anti-Idiotype Antibody Induced Cellular Immunity in Mice Transgenic for Human Carcinoembryonic Antigen," by Asim Saha, Sunil Chaterjee, Kenneth Foon and Malaya Chatterjee.

As the amount of biomedical information available in the literature continues to increase, databases that aggregate this information continue to grow in importance and scope. The population of databases can occur either through fully automated text mining approaches or through manual curation by human subject experts. We here report our experiences in populating the National Institute of Allergy and Infectious Diseases sponsored Immune Epitope Database and Analysis Resource ( IEDB, http://iedb.org), which was created in 2003, and as of 2012 captures the epitope information from approximately 99% of all papers published to date that describe immune epitopes (with the exception of cancer and HIV data). This was achieved using a hybrid model based on automated document categorization and extensive human expert involvement. This task required automated scanning of over 22 million PubMed abstracts followed by classification and curation of over 13 000 references, including over 7000 infectious disease-related manuscripts, over 1000 allergy-related manuscripts, roughly 4000 related to autoimmunity, and 1000 transplant/alloantigen-related manuscripts. The IEDB curation involves an unprecedented level of detail, capturing for each paper the actual experiments performed for each different epitope structure. Key to enabling this process was the extensive use of ontologies to ensure rigorous and consistent data representation as well as interoperability with other bioinformatics resources, including the Protein Data Bank, Chemical Entities of Biological Interest, and the NIAID Bioinformatics Resource Centers. A growing fraction of the IEDB data derives from direct submissions by research groups engaged in epitope discovery, and is being facilitated by the implementation of novel data submission tools. The present explosion of information contained in biological databases demands effective query and display capabilities to optimize the user experience. Accordingly, the development of original ways to query the database, on the basis of ontologically driven hierarchical trees, and display of epitope data in aggregate in a biologically intuitive yet rigorous fashion is now at the forefront of the IEDB efforts. We also highlight advances made in the realm of epitope analysis and predictive tools available in the IEDB. [ABSTRACT FROM AUTHOR]

In the preceding paper a population of lymphoid cells was identified which (1) were derived from germinal centres in the appendix, (2) were localized in follicular structures elsewhere, and (3) could perform as antibody-forming cell precursors. The present paper presents evidence (1) that germinal centres in the spleen and lymph nodes perform the same function as germinal centres in the appendix, and (2) that germinal centres are dependent upon a stream of cells derived from the bone marrow. A new hypothesis is put forward regarding the origin and cellular kinetics of the B-cell system in mammals. It is proposed that germinal centres throughout the body function as an essentially antigen-dependent amplification system for the B-cell population of lymphocytes. Implications of this hypothesis are discussed. [ABSTRACT FROM AUTHOR]

B cells have an important pathogenic role in the development of type 1 diabetes in the non-obese diabetic ( NOD) mouse. We have previously reported that NOD mice display an increased percentage of TACIhigh-expressing B cells compared with C57 BL/6 mice and this trait is linked to chromosomes 1 and 8. In this paper the genetic association of the transmembrane activator, calcium modulator and cyclophilin ligand interactor ( TACI) trait was confirmed using double congenic NOD. B6C1/Idd22 mice. TACI ligation by a proliferation-inducing ligand ( APRIL) has been shown to influence plasma cell differentiation, immunoglobulin production and isotype switch. Hence, the functional consequence of the up-regulation of TACI on NOD B cells was analysed both in vitro and in vivo. NOD B cells stimulated with APRIL showed an enhanced plasma cell differentiation and class switch to IgG and IgA compared with B cells from C57 BL/6 mice. Moreover, flow cytometry analyses revealed that germinal centre B cells in NOD failed to down-regulate TACI. Availability of the TACI ligand B-cell activating factor ( BAFF) has been shown to be a limiting factor in the germinal centre reaction. In line with this, upon immunization with 4-hydroxy-3-nitrophenylacetyl hapten-conjugated hen egg lysozyme, NOD mice produced higher titres of low-affinity antibodies compared with C57 BL/6 mice. This observation was supported by the detection of increased levels of BAFF in NOD germinal centres after immunization compared with C57 BL/6 by immunofluorescence. Our results support the hypothesis that increased TACI expression on NOD B cells contributes to the pathogenesis of type 1 diabetes in the NOD mouse. [ABSTRACT FROM AUTHOR]

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

We previously demonstrated that the majority ( ≥90%) of porcine ileal Peyer's patch (IPP) follicular cells are immature B cells destined to die by apoptosis, when incubated at 37°. In this paper we approached the mechanisms responsible for positive selection of porcine IPP follicular immature B-cell selection, by screening for various cell types, cytokines and polyclonal and monoclonal antibodies for promoting the survival of IPP B cells. Of these reagents, only CD3 cross-linked purified T cells from mesenteric lymph nodes were able to rescue IPP follicular B cells from apoptosis, although polyclonal anti-IPP lymphocyte antibodies delayed apoptosis. This survival effect could be reproduced simply by incubating IPP follicular B cells with soluble and cell membrane-expressed CD 154, an observation consistent with the demonstrated presence of CD40 and CD 154 on porcine IPP follicular B cells and activated T cells, respectively. The IPP follicular B cells rescued in this manner expressed a more mature surface marker phenotype. Immunohistology and fluorescence-activated cell sorter analysis demonstrated that subpopulations of IPP follicular T cells (less than 0.5%) express CD 154. Thus, perhaps unexpectedly, CD 154 on T cells may play a role in the positive selection of immature B cells in the porcine IPP. The origin and control of the activated T cells identified within the porcine IPP remains to be investigated. [ABSTRACT FROM AUTHOR]

As perhaps the staunchest advocates of repertoire purging as the central mechanism of immunological tolerance, we note with satisfaction a spate of recent, elegant papers which suggest an intrathymic clonal abortion model as the explanation for at least some examples of T-cell tolerance. This view agrees with the classical formulation of the Billingham-Brent-Medawar school of tolerance as a specific, central failure of immune responsiveness. Repertoire purging within the B-lymphocyte compartment remains much more controversial. There is no doubt that experimental models exist where the B cell is the reversible target of tolerance induction. The question is, in view of the ease of inducing autoantibody formation both in vivo and in vitro, just how relevant are such clonal anergy mechanisms to authentic self-tolerance? Arguments are presented that there must be two windows of tolerance susceptibility in the ontogeny of the B cell; one while it is maturing in the bone marrow, to prevent autoreactivity of high affinity to important accessible self-antigens; and a second soon after activation of pre-memory cells by exogenous antigen, to prevent fortuitous mutations towards high-affinity anti-self-reactivity establishing a forbidden clone. [ABSTRACT FROM AUTHOR]

A potent immunosuppressor factor, known as SER (suppressive E-receptor factor) has been identified in the body fluids of cancer patients. SER has been proven to be immunochemically analogous to the fetal form of haptoglobin. In this paper, we examine the role of SER immune suppressor in the immune surveillance mechanism of the host, using an affinity-purified SER. As shown in this study, SER, at µg/ml concentrations, inhibits the T-cell proliferation induced with either monoclonal or polyclonal T-cell activators in vitro in human, and also inhibits the primary antibody response to T-dependent antigens in vivo in mice. Likewise, SER also inhibits the immunoglobulin synthesis of human B lymphocytes induced by a B-cell mitogen, pokeweed mitogen, in the presence of a tumour promoter, phorbol myristate acetate (PMA). In contrast to the T-dependent antibody response in vivo in mice or T-dependent mitogen response in vitro in human, SER does not interfere with the T-independent antibody responses to DNP-Ficoll or TNP-LPS in mice. SER also interferes with the natural killer cell function of human peripheral blood mononuclear cells. Although SER inhibits the phagocytic functions of human peripheral neutrophils, it requires at least 10-20 times the concentration of SER present in normal human plasma. Since this concentration of SER is attainable in the sera of solid tumour-bearing patients, highly elevated levels of SER could predispose the patients to microbial infections as well. This study demonstrates that purified SER manifests multi-faceted down-regulatory effects on the defence mechanism of hosts, thereby it could compromise the patients' cell-mediated immunity in vivo. [ABSTRACT FROM AUTHOR]

Reagents for the identification of rabbit cell markers have been developed at a relatively slow rate. In this paper, rabbit cells are being characterized by polyclonal antibodies against a Tall antigen (RTLA), a B-cell antigen (RABELA) and an analogue of murine Ia antigen. A number of monoclonal antibodies, specific for lymphocytes and/or bone marrow and/or polymorphonuclear leucocytes, have been used for the analysis of cells with identifiable membrane antigens. Populations that have cells with two of the above antigens in the membranes were identified. To these ends, complement-mediated cell kill by antisera alone and in mixtures was employed. [ABSTRACT FROM AUTHOR]

CBA/N mice harbour an X-linked B cell defect which is transmitted by CBA/N female mice to their hybrid male progeny. These mice mount normal responses to thymus-dependent (TD) and some thymus-independent (TI-1) antigens, while the response to TI-2 antigens is absent. Hapten-specific plaque-forming cell (PFC) responses to TD antigens can be blockaded by concomitant exposure of these mice to TI-2 antigens bearing the same hapten. This paper investigates in defective mice the blockade of their response to TNP3-LPS (trinitrophenylated lipopolysaccharide, a TI-1 antigen), imposed by DNP59-Ficoll (dinitrophenylated Ficoll, a TI-2 antigen). The effectiveness of the blocking agent, DNP59-Ficoll, differed in various inbred mouse strains: CBA/N × C3H/HeN F1 male > CBA/N female > CBA/N · C3H/HeN F1 female. The role of T cells in the observed hapten-specific blockade phenomenon was investigated using athymic CBA/N nude mice and a B cell tolerogen. Our findings indicate that T cell participation is not essential for the blockade of CBA/N PFC responses and they suggest that direct blockade of TI- and TD-responsive B cell populations is likely to occur. [ABSTRACT FROM AUTHOR]

This paper uses B-lymphocyte cloning methods to quantify the effects of anti-μ chain antibody on immature and mature B cells. Nude mouse spleen lymphocytes were incubated with various concentrations of sheep anti-mouse μ chain antibody for times varying from 10 min to 24 h. They were then washed and plated in the agar B-cell colony formation assay. Five to six days later, control B cells had developed into colonies with a plating efficiency of about 5%. B cells from newborn mice pretreated with anti-μ yielded fewer colonies. Remarkably low concentrations sufficed to inhibit subsequent mitogenesis. For example, 3 μg/ml acting for 1 h or 0.1 μg/ml acting for 24 h gave > 50% inhibition. Adult B cells were about thirty-fold more resistant to negative signalling. Immature cells became more profoundly inhibited as anti-μ treatment was prolonged. Anti-Ia or anti-H2 antibodies, in the absence of complement, did not deliver a negative signal. Anti-μ pretreatment also reduced the capacity of immature B cells to form clones of anti-hapten antibody-forming cells in a liquid microculture system where the triggering stimulus was a T-cell independent antigen. Mature 'T-independent' B cells were not inhibited. Populations of hapten-specific B cells prepared by the hapten-gelatin method were investigated in the agar cloning system. Pretreatment of immature cells with anti-μ reduced their capacity to form colonies, this subpopulation of cells behaving like unfractionated B cells. Furthermore, hapten--HGG delivered a negative signal also. Mature hapten-specific cells or unfractionated immature spleen cells formed normal numbers of colonies following hapten HGG treatment. Overall, the studies support the view that anti-μ antibody and hapten--HGG deliver strong negative signals to immature but not mature cells with appropriate receptors. The value of anti-μ as a model, universal tolerogen was supported. Fluorescence-activated cell sorter (FACS) analysis was performed to study the relationships between functional inhibition and Ig receptor modulation. We confirmed that the IgM receptors of immature B cells are more readily modulated by anti-μ antibody than those of mature cells. Furthermore, the receptor regeneration could be partially inhibited amongst immature but not mature B cells. There was not a close quantitative relationship between the degree of modulation and the degree of functional inhibition. The results did not support the view that irreversible receptor modulation as such was the cause of functional inhibition. [ABSTRACT FROM AUTHOR]

Examines various types of T lymphocyte functions in the spleens of mice infected four days previously with Friend virus (FV) in order to analyze its effect on the antibody response. Finding that infection does not reduce the percentage of T lymphocytes in the spleen, nor the ability to respond to phytohemagglutinin (PHA); Results suggesting that FV does not affect spleen T lymphocyte proliferation or helper function; Conclusion that the immune defect resides in the B lymphocytes.

For most antisera a linear relationship can be shown between log antigen concentration and the log concentration of antibody required to bind half the available antigen. This paper shows that the slope of this line, s, is related to the distribution of individual antibody clonotypes of different affinity. It is argued that the general form of the distribution approximates to exponential (rather than for example Gaussian) and that this indicates a requirement for some force to be exerted through the antigen-receptor bond in order to activate a B cell. An alternative parameter, A, which gives more weight to high affinity clonotypes, is offered in place of K0 as a measure of the avidity and biological effectiveness of an antiserum. [ABSTRACT FROM AUTHOR]

Mice infected with African trypanosomes produce exceptionally large amounts of serum IgM, a major part of which binds to non-trypanosome antigens such as trinitrophenol and single-strand DNA. In this paper, we describe that in cattle infected with Trypanosoma congolense and T. vivax, similar antibodies are found, although they bind mainly to protein antigens, such as β-galactosidase, ovalbumin and ferritin. The parasite non-specific IgM antibodies appear around the same time as the parasite-specific antibodies, but their origin and function are not clear. We tested the hypothesis that CD5+ B cells (or B-1 cells), which increase during trypanosome infections in cattle, are responsible for production of antibodies to non-trypanosome antigens. Splenic CD5+ and CD5- B cells from infected cattle were sorted and tested in a single cell blot assay. The numbers of immunoglobulin-secreting cells were similar in both B-cell populations. However, antibodies with reactivity for non-trypanosome antigens were significantly more prevalent in the CD5+ B-cell fraction and were exclusively IgM. The preference for production of these antibodies by CD5+ B cells and the expansion of this subpopulation during infections in cattle, strongly suggest that CD5+ B cells are the main source of trypanosome non-specific antibodies. We propose that these antibodies are natural, polyreactive antibodies that are predominantly secreted by CD5+ B cells. Since B-1 cells are up-regulated in many states of immune insufficiency, the immunosuppression associated with trypanosome infections may be responsible for the increase of this subset and the concomitant increase in trypanosome non-specific antibodies. [ABSTRACT FROM AUTHOR]

This paper describes a model for investigation of the functional implications of B-cell activation for antigen presentation. Mixed lymphocyte cultures were used to assess the ability of freshly isolated B cells, mitogen-activated B cells and Epstein Burr virus (EBV)-transformed B-cell lines to stimulate the activation and proliferation of allogeneic T cells under a variety of experimental conditions. It was found that resting B cells presented antigen poorly, while activated cells were highly immunogenic. Paraformaldehyde fixation completely eliminated antigen presentation by resting B cells, despite constitutive expression of class II MHC antigens. However, fixation had little effect on antigen presentation by activated B cells that expressed B7-1 and B7-2 in addition to class II major histocompatibility complex (MHC) molecules. Arrest of B-cell activation by serial fixation after treatment with F(ab′)2 fragments of goat anti-human IgM produced cells with variable antigen-presenting capacity. Optimal antigen presentation was observed for cells fixed 72hr after the initiation of B-cell activation. Although both BT-1 and B7-2 antigen expression increased after B-cell activation, it was found that the rate of T-cell proliferation correlated most closely with B7-2 expression. Stimulation of T cells by fixed activated B lymphocytes could be blocked by antibodies directed at class II MHC molecules, indicating involvement of the T-cell antigen receptor. In addition, T-cell proliferation was inhibited by antibodies specific for B7-1 and B7-2 and by the fusion protein CTLA4-Ig, demonstrating a requirement for CD28 signal transduction. The sole requirement of B7 family expression for antigen presentation by B lymphocytes was shown by demonstration of T-cell stimulation by fixed resting B cells in the presence of CD28 antibody as a source of artificial costimulation. [ABSTRACT FROM AUTHOR]

Evidence from in vitro studies indicates that immunoglobulin A (IgA) responses are highly T dependent, yet investigations of the requirement for cognate help For IgA responses in tiro have not previously been undertaken. Experiments reported in this paper employ hapten-carrier immunization of individual Peyer's patches (PP), the site of generation of IgA antibody-containing cells (ACC) responding to lumenal antigenic challenge in the intestine, to determine the requirements for T-cell and B-cell priming under normal physiological conditions in vivo. These experiments demonstrate that both hapten-specific B-cell priming and carrier-specific T-cell priming in PP are required for an IgA-specific anti-hapten ACC response in the intestinal lamina propria to subsequent lumenal challenge with hapten-carrier conjugate. These results confirm that IgA B-cell induction in PP requires cognate T-cell help. An IgA ACC response can also be obtained when hapten and carrier priming occur in different PP, providing functional significance for our previous observations that PP-derived T-helper cells are able to migrate between PP after priming. [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]

B lymphocyte‐mediated humoral immune response is essential for protection against infectious diseases. Deeper research in B cell biology, particularly metabolism is required for the better understanding of its properties in homeostasis and in diseases. Emerging immunometabolism, including anabolism and catabolism, has tremendously impacts on immune cells from development to function and markedly advances our view on immunoregulation. Growing evidence suggests that the ultimate effect of intracellular metabolism on immune cell functions is not only influenced by the external stimuli but also by the balance of the different metabolic pathways. However, B cell immunometabolism is not deeply investigated like T cells. The complex development and differentiation processes of B cell subsets have left many untouched, but fundamental aspects in B cell metabolism. Available evidence demonstrated that the intracellular metabolism has the ubiquitous impact on B cell fate and function decisions at the transcriptional regulation and signal transduction processes. In this review, we update the recent development in the immunometabolism of B cells with the latest findings including the immune‐metabolic steering on B cell development, differentiation, and function skewing, and emphasis on how immunometabolism landscape may shape B cell functions in metabolic, autoimmune, and inflammatory disorders. The metabolic interaction of B cells with other immune cells in disease context will also be discussed. [ABSTRACT FROM AUTHOR]

Conventional dendritic cells (cDC) are bone marrow‐derived immune cells that play a central role in linking innate and adaptive immunity. cDCs efficiently uptake, process and present antigen to naïve T cells, driving clonal expansion of antigen‐specific T‐cell responses. In chicken, vital reagents are lacking for the efficient and precise identification of cDCs. In this study, we have developed several novel reagents for the identification and characterization of chicken cDCs. Chicken FLT3 cDNA was cloned and a monoclonal antibody to cell surface FLT3 was generated. This antibody identified a distinct FLT3HI splenic subset which lack expression of signature markers for B cells, T cells or monocyte/macrophages. By combining anti‐FLT3 and CSF1R‐eGFP transgenic expression, three major populations within the mononuclear phagocyte system were identified in the spleen. The cDC1 subset of mammalian cDCs express the chemokine receptor XCR1. To characterize chicken cDCs, a synthetic chicken chemokine (C motif) ligand (XCL1) peptide conjugated to Alexa Fluor 647 was developed (XCL1AF647). Flow cytometry staining of XCL1AF647 on splenocytes showed that all chicken FLT3HI cells exclusively express XCR1, supporting the hypothesis that this population comprises bona fide chicken cDCs. Further analysis revealed that chicken cDCs expressed CSF1R but lacked the expression of CSF2R. Collectively, the cell surface phenotypes of chicken cDCs were partially conserved with mammalian XCR1+ cDC1, with distinct differences in CSF1R and CSF2R expression compared with mammalian orthologues. These original reagents allow the efficient identification of chicken cDCs to investigate their important roles in the chicken immunity and diseases. [ABSTRACT FROM AUTHOR]

B‐cell development undergoes a series of steps from the bone marrow to the secondary lymphoid organs. A defect in B‐cell development can lead to immunodeficiency or malignant disorders, such as leukaemia or lymphoma. Long non‐coding RNAs have been reported to act as important regulators of many pathological processes. However, very little is known regarding the role of lncRNAs during B‐cell development and the regulation of their expression. In this study, we explored the expression and role of lncRNA Gme00492 in B‐cell development. We observed that lnc00492 was highly expressed in B‐cell development and primarily expressed in the nucleus. Lnc00492‐deficient mice had fewer marginal zone B cells in the spleen, likely due to a developmental block. Importantly, lnc00492 interacts with CTBP1 and targets it for ubiquitination and degradation during B‐cell development, whereas the transcriptional corepressor factor CTBP1 plays a critical role in Notch2 signalling. Thus, we identified a novel regulatory axis between lnc00492 and CTBP1 in B cells, suggesting that lnc00492 is essential for marginal zone B‐cell development. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease without known cure that primarily affects synovial joints. RA has a prevalence of approximately 1% of the population worldwide. A vicious circle between two critical immune cell types, B cells and neutrophils, develops and promotes disease. Pathogenic anti‐citrullinated protein antibodies (ACPA) directed against a range of citrullinated epitopes are abundant in both plasma and synovial fluid of RA patients. In addition to stimulating numerous cell types, ACPA and other autoantibodies, notably rheumatoid factor, form immune complexes (ICs) that potently activate neutrophils. Attracted to the synovium by abundant chemokines, neutrophils are locally stimulated by ICs. They generate cytokines and release cytotoxic compounds including neutrophil extracellular traps (NETs), strands of decondensed chromatin decorated with citrullinated histones and granule‐derived neutrophil proteins, which are particularly abundant in the synovial fluid. In this way, neutrophils generate citrullinated epitopes and release peptidylarginine deiminase (PAD) enzymes capable of citrullinating extracellular proteins in the rheumatic joint, contributing to renewed ACPA generation. This review article focusses on the central function of citrullination, a post‐translational modification of arginine residues in RA. The discussion includes ACPA and related autoantibodies, somatic hypermutation‐mediated escape from negative selection by autoreactive B cells, promotion of the dominance of citrullinated antigens by genetic and lifestyle susceptibility factors and the vicious circle between ACPA‐producing pathogenic B cells and NET‐producing neutrophils in RA. [ABSTRACT FROM AUTHOR]

Summary: Immunologists are sometimes guilty of describing the innate immune response as 'non‐specific'. What we really mean is that the pattern recognition receptors of innate immune cells are not able to recombine and mutate to bind the spectacular range of molecular patterns that can be recognised by B and T cells. So, while it may be accurate to describe the innate immune response as less specific than adaptive immunity, even this belies the emerging complexity of the receptors and receptor complexes that control inflammatory responses. This complexity is necessary to recognise danger, and therefore successfully initiate proportionate inflammatory responses to cellular damage or against potential pathogens. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is currently thought to arise by interactions between genetic susceptibility and environmental factors. Infections in general trigger autoimmune responses causing clinical manifestations of disease. However, as a result of regulatory T (Treg)‐ and regulatory B (Breg)‐cell induction, helminth infections tend to dampen disease activity. IL‐35, the newest member of the IL‐12 family, is an inhibitory cytokine composed of an EBI3β chain subunit, and an IL‐12p35 subunit. The aim of this study was to investigate the role of IL‐35 during parasite infections occurring in individuals with MS. Numbers of IL‐35‐producing Breg cells are higher in CSF from helminth‐infected than from uninfected MS subjects, a finding associated with decreased MRI disease activity. Interestingly, stimulation of CD19+ B cells with IL‐35 promotes conversion of these cells to Breg cells producing both IL‐35 and IL‐10. Coculture of B cells from helminth‐infected MS patients inhibits proliferation of Th1 and Th17 myelin peptide‐specific T cells, as well as production of IFN‐γ and IL‐17. Following activation, CD4+CD25+ Treg cells significantly upregulate expression of EBI3 and IL‐12p35 mRNA. Furthermore, CD4+CD25− T cells activated in the presence of IL‐35 induce a population of cells with regulatory function, known as iTR35. Finally, B cells from normal individuals cultured in vitro in the presence of the helminth antigen SEA increase expression of the transcription BATF, IRF4 and IRF8, acquiring a pattern similar to that of IL‐35 Breg cells. These data highlight the important immunoregulatory effects of IL‐35 on both Breg and Treg cells, observed in helminth‐infected MS subjects. [ABSTRACT FROM AUTHOR]

It is important to characterize novel proteins involved in T‐ and B‐cell responses. Our previous study demonstrated that a novel protein, Musmusculus Gm40600, reduced the proliferation of Musmusculus plasmablast (PB)‐like SP 2/0 cells and B‐cell responses induced in vitro by LPS. In the present study, we revealed that Gm40600 directly promoted CD4+ T‐cell responses to indirectly up‐regulate B‐cell responses. Importantly, we found that CD4+ T‐cell responses, including T‐cell activation and differentiation and cytokine production, were increased in Gm40600 transgenic (Tg) mice and were reduced in Gm40600 knockout (KO) mice. Finally, we demonstrated that Gm40600 promoted the Ahnak‐mediated calcium signalling pathway by interacting with Ahnak to maintain a cytoplasmic lateral location of Ahnak in CD4+ T cells. Collectively, our data suggest that Gm40600 promotes CD4+ T‐cell activation to up‐regulate the B‐cell response via interacting with Ahnak to promote the calcium signalling pathway. The results suggest that targeting Gm40600 may be a means to control CD4+ T‐cell‐related diseases. [ABSTRACT FROM AUTHOR]

B cells and dendritic cells, lacking functional Wiskott-Aldrich syndrome protein (WASP), have aberrant formation of membrane protrusions. We hypothesized that protrusions may play a role in antigen presentation, and consequently, that impaired antigen presentation may be an underlying factor of the immune deficiency in patients with Wiskott-Aldrich syndrome. In this paper, we investigated the antigen presentation capacity of B cells and dendritic cells from WASP knockout mice, using soluble and particulate antigen, to CD4[SUP+] T cells from T-cell receptor transgenic DO11.10 mice. As antigen we used soluble ovalbumin (OVA), a peptide thereof (amino acids 323-339) or bacteria expressing OVA. We tound that WASP-deficient B cells and dendritic cells efficiently processed and presented soluble OVA protein as well as its peptide in vitro, inducing proliferation and cytokine production from CD4[SUP+] T cells. Antigen presentation of soluble protein was efficient also in vivo, because immunization of WASP-deficient mice with OVA elicited proliferation of transferred, fluorescent-labelled, CD4[SUP+] T cells. Although we could detect uptake of bacteria in dendritic cells, processing and presentation of bacterial-expressed OVA was impaired in WASP-deficient dendritic cells. In conclusion, our data suggest that WASP is not needed for processing and presentation of soluble antigen, but that efficient presentation of particulate antigen require WASP. [ABSTRACT FROM AUTHOR]

Presents abstracts of research papers on B-cell biology, published in the December 2002 supplement of 'Immunology.' 'Regulatory B cells,' by D. Gray, et al; 'RNA analysis of receptor editing,' by D. Nemazee, et al.

Non‐immune cells are increasingly recognized as important in regulating immunity, but the role of red blood cells (RBC) remains relatively unexplored, despite their abundance in the circulation and a cell surface rich in potential ligands. Here, we determine whether RBC influence the activation state of human B cells. Separation of RBC from peripheral blood mononuclear cells increased B‐cell expression of HLA‐DR/DP/DQ, whilst reconstitution reduced the levels of B‐cell activation markers HLA‐DR/DP/DQ, CD86, CD69 and CD40, as well as decreasing proliferative responses and IgM secretion. Inhibition of B cells required contact with RBC and was abrogated by either removal of sialic acids from RBC or blocking the corresponding lectin receptor CD22 on B cells. Chronic lymphocytic leukaemia B cells express low levels of CD22 and were less susceptible to inhibition by RBC, which may contribute to their activated phenotype. Taken together, the results identify a novel mechanism that may suppress inappropriate responsiveness of healthy B cells whilst circulating in the bloodstream. [ABSTRACT FROM AUTHOR]

Major histocompatibility complex (MHC) restrictions in the secondary antibody response in vitro to the soluble protein antigen trinitrophenyl keyhole limpet haemocyanin (TNP-KLH) were investigated in this study. Experimental conditions were employed which ensured that co-operation between KLH-primed T cells and TNP-primed B cells was possible only through linked recognition of carrier and haptenic determinants. Under such conditions co-operation between T and B cells appears to be MHC-restricted.

A positive association has been observed in Igh allotype ‘congenic’ mice between skin graft rejection and a block to effective T-B co-operation in the development of both IgM and IgG responses to sheep erythrocytes. Mismatch of Igh alone is insufficient for such a block to become apparent since pairs of Igh-allotype congenic strains of mice which reciprocally accept skin grafts for at least 5 weeks, show successful positive co-operation (help) between T and B cells. The observed block is manifest both during the education (priming) of T cells in irradiated (first stage) recipients and during co-operation between primed T cells and unprimed B cells in second stage irradiated ‘syngeneic’ recipients. [ABSTRACT FROM AUTHOR]

Incorporation of [14C]-thymidine into mouse lymph node cells stimulated with either Concanavalin A or lipopolysaccharide in serum-free medium was markedly enhanced by the addition of transferrin. Thymidine incorporation was similar in transferrin-containing serum-free medium and in medium containing 5% foetal calf serum. Transferrins from both homologous and heterologous species were equally effective, but iron-binding half-molecules of transferrin, and low molecular weight iron chelates produced no enhancement. The optimal response was obtained with 10-50 pg/mi of transferrin, and with 30%-70% iron saturation. Although the major function of transferrin in lymphocyte cultures is probably to supply iron, it may also fulfil other functions. [ABSTRACT FROM AUTHOR]

T cells involved in specific and nonspecific co-operation belong to a long-lived population. However, under conditions of limiting dilution of T cells it is not a common event to detect both types of co-operative event in a single microculture well. Likewise, as far as specific co-operation is concerned, the simultaneous expression of both direct and indirect PFC responses in a single microculture well is also unusual. Estimates obtained of the number of PFC generated by one T cell in specific co-operation correspond well to those generated by a single B cell; and it would seem that under conditions of the microculture system there is a marked restriction in the number of B cells that a single T cell may interact with in the short term. This restriction seems to be of a one T-cell to one B-cell relationship. [ABSTRACT FROM AUTHOR]

This study addresses itself to the problem of antibody formation in vitro by mouse splenic B lymphocytes enriched for reactivity to the hapten NIP by the hapten-gelatine binding and melting technique of Haas and Layton (1975). Small numbers of NIP-gelatine-bound B cells were placed in micro- cultures either by bulk dispensing of dilute cell suspensions, or by micromanipulation under direct microscopic visualization. Antibody formation was induced by the T cell-independent hapten-protein conjugate NIP-polymerized flagellin, using 104 thymus cells per microlitre as 'filler' cells. The frequency of precursors of NIP-specific antibody- forming cells among bound cells was about 2.2 × 10-2 (one cell in forty-five) by both statistical and direct evaluation, after adjustment for a background frequency of 6-10 × 10-8 precursors in the thymus filler cells. Single clones commenced antibody secretion asynchronously, as shown by the fact that the incidence of positive cultures continued to rise over the whole three days of culture, and that very small clones of one to four plaque-forming cells (PFC) were still found on day 3. The mean PFC number per positive culture rose from 1.2 at day 1 to 4.7 at day 2 and about 20 at day 3. Negative feedback, presumably mediated by antigen-antibody complexes, was shown to be a powerful effect in microcultures containing bound cells. It was evident with 250 cells per well (five clones) and the effect was progressive, such that with 10⊃ bound cells per well, plaque numbers were 40-50 per cent of their potential optimum; with 104, 10 per cent, and 105, 1 per cent. With routine techniques of harvesting of cultured cells, a failure to disperse PFC uniformly into single cells was noted. Groups of two or more large cells of very similar morphology were frequently observed at the centre of haemolytic plaques. Micromanipulation studies revealed that essentially all large cells at the centre of plaques were PFC. It was found that a routine plaque count underestimated the true PFC number per culture by a factor of 2. In the absence of negative feedback, the system is capable of generating one PFC per two input B lymphocytes. This is by far the most efficient plaque- generating system yet described, and contrasts with a yield of one PFC per 104 input cells in most typical tissue culture systems. Reasons for believing that both the culture and the enrichment systems can be further improved are discussed, and the potential of the method for understanding the cell and molecular biology of lymphocyte triggering is described. [ABSTRACT FROM AUTHOR]

Bone marrow cells and thymus cells were observed in cell transfer expehments to collaborate in the production of anti-BSA antibodies. The target cells for tolerance induction either with a 'low dose' of antigen (100 µg of deaggregated BSA once a week × 5) or with a 'high dose' (a single injection of 5000 µg) were identified by the same technique. In 'low dose' tolerance, some indication was obtained that thymus-derived cells in peripheral lymphoid systems were the target cells; bone marrow-derived cells appeared not to be so susceptible, and the cells residing in thymus or bone marrow seemed to remain unimpaired, in contrast, the injection of a 'high dose' of tolerogen rendered both types of cells in spleen, thymus cells and bone marrow cells, unresponsive or hyporesponsive in parallel with one another. [ABSTRACT FROM AUTHOR]

Summary: The circadian clock provides organisms with the ability to track time of day, allowing them to predict and respond to cyclical changes in the external environment. In mammals this clock consists of multiple auto‐regulatory feedback loops generated by a network of circadian clock proteins. This network provides the fundamental basis for rhythms in behaviour and physiology. This clockwork machinery exists in most cells, including those of the immune system. In recent years evidence has emerged highlighting the important role of molecular clocks in dictating the response of immune pathways. While initial work highlighted the effect of the clock in the 'first line of defence', the innate immune system, it has become increasingly apparent that it also plays a role in the more tailored, later‐stage adaptive immune response. This review provides an overview of the role of the circadian cycle in the adaptive immune response. We interrogate the depth of knowledge on cell intrinsic clocks within adaptive immune cells and how these cells may be temporally directed by extrinsic rhythmic signals. We discuss the role of the circadian clock in diseases associated with adaptive immunity such as multiple sclerosis, asthma and parasitic infection. We also discuss the current knowledge on timing of vaccination, and the implications this may have on how we can harness and modulate temporal gating of the adaptive immune response in a clinical setting. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19) is a respiratory disorder caused by the highly contagious severe acute respiratory syndrome coronavirus 2. The immunopathological characteristics of patients with COVID‐19, either systemic or local, have not been thoroughly studied. In the present study, we analysed both the changes in the number of various immune cell types as well as cytokines important for immune reactions and inflammation. Our data indicate that patients with severe COVID‐19 exhibited an overall decline of lymphocytes including CD4+ and CD8+ T cells, B cells and natural killer cells. The number of immunosuppressive regulatory T cells was moderately increased in patients with mild COVID‐19. Interleukin‐6 (IL‐6), IL‐10 and C‐reactive protein were remarkably up‐regulated in patients with severe COVID‐19. In conclusion, our study shows that the comprehensive decrease of lymphocytes, and the elevation of IL‐6, IL‐10 and C‐reactive protein are reliable indicators of severe COVID‐19. [ABSTRACT FROM AUTHOR]

Summary: Nuclear receptor peroxisome proliferator‐activated receptor γ (PPAR‐γ) activation can prevent immunoinflammatory disorders and diabetes. B cells play protective roles during inflammation as well. However, the roles of endogenous PPAR‐γ in the regulatory properties of B cells to relieve inflammation remain unknown. Here, we developed B‐cell‐specific PPAR‐γ knockout (B‐PPAR‐γ−/−) mice and found that the conditional deletion of PPAR‐γ in B cells resulted in exaggerated contact hypersensitivity (CHS). Meanwhile, interferon‐γ (IFN‐γ) of CD4+CD8+ T cells was up‐regulated in B‐PPAR‐γ−/− mice in CHS. This showed that the regulatory function of B cells in B‐PPAR‐γ−/− mice declined in vivo. Whereas splenic CD5+CD1dhi regulatory B‐cell numbers and peripheral regulatory T‐cell numbers were not changed in naive B‐PPAR‐γ−/− mice. Loss of PPAR‐γ in B cells also did not affect either CD86 or FasL expression in splenic CD5+CD1dhi regulatory B cells after activation. Notably, interleukin‐10 (IL‐10) production in CD5+CD1dhi regulatory B cells reduced in B‐PPAR‐γ‐deficient mice. In addition, functional IL‐10‐producing CD5+CD1dhi regulatory B cells decreased in B‐PPAR‐γ−/− mice in the CHS model. These findings were in accordance with augmented CHS. The current work indicated the involvement of endogenous PPAR‐γ in the regulatory function of B cells by disturbing the expansion of IL‐10‐positive regulatory B cells. B‐cell‐specific deletion of PPAR‐γ resulted in exaggerated contact hypersensitivity (CHS). This was due to the impaired expansion of IL‐10‐positive regulatory B cells after activation. Endogenous PPAR‐γ is involved in the regulatory function of B cells. [ABSTRACT FROM AUTHOR]

Summary: Mouse models of multiple sclerosis (MS) have shown the importance of interleukin‐10 (IL‐10) ‐producing regulatory B (Breg) cells in dampening disease activity and inhibiting disease initiation and progression. In MS and other autoimmune diseases decreased frequency and functionality of Breg cells correlate with disease activity and the percentage of IL‐10‐producing Breg cells decreases during relapse and normalizes in remission. Optic neuritis (ON) is a common first clinical manifestation of MS and IL‐10‐producing Breg cells may be crucial in the transition from ON to MS, we therefore investigate the frequency and function of Breg cells in ON as a clinical model of early demyelinating disease. B cells were purified from 27 patients with ON sampled close to symptom onset (median 23 days, range 7–41 days) and 13 healthy controls. The B cells were stimulated and cultured for 48 hr with CD40 ligand and CpG before measurement of intracellular IL‐10 and the surface markers CD19, CD1d, CD5, CD24, CD38 and CD27 by flow cytometry. The frequency of B‐cell subsets was analysed in peripheral blood and cerebral spinal fluid (CSF) of patients. Sixty‐five per cent of the IL‐10‐producing Breg cells co‐expressed CD24 and CD38, and only 14% were CD24high CD27+, suggesting that the naive B cells are the primary source of IL‐10 in the B‐cell culture, followed by memory cells in both healthy controls and patients. The frequency of naive CD19+ CD24+ CD38+ Breg cells was higher in patients with ON compared with controls. The ability of Breg cells to produce IL‐10 was at normal levels in both ON patients with high risk and those with low risk of progression to MS. We found no correlation between Breg cell function and the presence of brain white matter lesions by magnetic resonance imaging or CSF oligoclonal bands indicative of ON patients carrying a higher risk of conversion to MS. The frequencies of IL‐10‐producing B cells did not correlate with the conversion to MS at 2‐year follow up. Interleukin‐10 was primarily produced by naive and memory B cells. The frequency of IL‐10‐secreting B cells did not correlate with risk factors of MS. Breg cell function at clinical onset of ON is not a determining factor for conversion to MS. Interleukin 10 (IL‐10) prodicing regulatory B cells have been found to ameliorate the disease progression in animal models of multiple sclerosis. We investigated the frequency of regulatory B cells in healthy controls and in patients with optic neuritis, which is a common first manifestation in multiple sclerosis. There were no differences in the IL‐10 production by B cells in healthy controls and optic neuritis patients with a high risk of progressing to multiple sclerosis. [ABSTRACT FROM AUTHOR]

Summary: Genetic variation at HLA‐DRB1 is a risk factor for visceral leishmaniasis (VL) caused by Leishmania donovani. The single nucleotide polymorphism rs9271252 upstream of the DRB1 gene provides a perfect tag for protective versus risk HLA‐DRB1 four‐digit alleles. In addition to the traditional role of the membrane‐distal region of HLA class II molecules in antigen presentation and CD4 T‐cell activation, the membrane‐proximal region mediates 'non‐traditional' multi‐functional activation, differentiation, or death signals, including in DR‐expressing T cells. To understand how HLA‐DR contributes to disease pathogenesis, we examined expression at the protein level in circulating myeloid (CD14+, CD16+) and lymphoid (CD4+, CD8+, CD19+) cells of VL patients (pre‐ and post‐treatment) compared with endemic healthy controls (EHC). Although DR expression is reduced in circulating myeloid cells in active disease relative to EHC and post‐treatment groups, expression is enhanced on CD4+ DR+ and CD8+ DR+ T cells consistent with T‐cell activation. Cells of all myeloid and lymphoid populations from active cases were refractory to stimulation of DR expression with interferon‐γ (IFN‐γ). In contrast, all populations except CD19+ B cells from healthy blood bank controls showed enhanced DR expression following IFN‐γ stimulation. The rs9271252 genotype did not impact significantly on IFN‐γ‐activated DR expression in myeloid, B or CD8+ T cells, but CD4+ T cells from healthy individuals homozygous for the risk allele were particularly refractory to activated DR expression. Further analysis of DR expression on subsets of CD4+ T cells regulating VL disease could uncover additional ways in which pleiotropy at HLA DRB1 contributes to disease pathogenesis. Genetic variation at HLA‐DRB1 is a risk factor for visceral leishmaniasis caused by Leishmania donovani. The single nucleotide polymorphism rs9271252 upstream of the DRB1 gene provides a perfect tag for protective versus risk HLA‐DRB1 four‐digit alleles. Here we show that CD4+ T cells from individuals homozygous for the risk allele at rs9271252 are particularly refractory to activated DR expression. [ABSTRACT FROM AUTHOR]

Summary: An increasing body of literature supports a role for neutrophils as players in the orchestration of adaptive immunity. During acute and chronic inflammatory conditions, neutrophils rapidly migrate not only to sites of inflammation, but also to draining lymph nodes and spleen, where they engage bidirectional interactions with B‐ and T‐lymphocyte subsets. Accordingly, a relevant role of neutrophils in modulating B‐cell responses under homeostatic conditions has recently emerged. Moreover, specialized immunoregulatory properties towards B or T cells acquired by distinct neutrophil populations, originating under pathological conditions, have been consistently described. In this article, we summarize the most recent data from human studies and murine models on the ability of neutrophils to modulate adaptive immune responses under physiological and pathological conditions and the mechanisms behind these processes. In this article, we summarize the most recent data from human studies and murine models on the ability of neutrophils to modulate B‐ and T‐cell responses under physiological and pathological conditions and the mechanisms behind these processes. [ABSTRACT FROM AUTHOR]

Summary: B lymphocytes, known as antibody producers, mediate tumor cell destruction in the manner of antibody‐dependent cell‐mediated cytotoxicity; however, their anti‐tumor function seems to be weakened during tumorigenesis, while the underlying mechanisms remain unclear. In this study, we found that IgG mediated anti‐tumor effects, but IgG‐producing B cells decreased in various tumors. Considering the underlying mechanism, glycometabolism was noteworthy. We found that tumor‐infiltrating B cells were glucose‐starved and accompanied by a deceleration of glycometabolism. Both inhibition of glycometabolism and deprivation of glucose through tumor cells, or glucose‐free treatment, reduced the differentiation of B cells into IgG‐producing cells. In this process, special AT‐rich sequence‐binding protein‐1 (SATB1) was significantly silenced in B cells. Down‐regulating SATB1 by inhibiting glycometabolism or RNA interference reduced the binding of signal transducer and activator of transcription 6 (STAT6) to the promoter of germline Cγ gene, subsequently resulting in fewer B cells producing IgG. Our findings provide the first evidence that glycometabolic inhibition by tumorigenesis suppresses differentiation of B cells into IgG‐producing cells, and altering glycometabolism may be promising in improving the anti‐tumor effect of B cells. IgG‐producing B cells exerted an anti‐tumor effect, but dramatically decreased in various tumors. Glucose deprivation caused by tumorigenesis down‐regulated the glucose metabolism of B cells and then impaired their generation into IgG‐producing B cells. SATB1, known as a cell‐type‐specific 'genomic organizer', was down‐regulated in the glucose‐starved B cells and responsible for the deficiency generation of IgG‐producing B cells in tumors. [ABSTRACT FROM AUTHOR]

Summary: High‐throughput sequencing of the DNA/RNA encoding antibody heavy‐ and light‐chains is rapidly transforming the field of adaptive immunity. It can address key questions, including: (i) how the B‐cell repertoire differs in health and disease; and (ii) if it does differ, the point(s) in B‐cell development at which this occurs. The advent of technologies, such as whole‐genome sequencing, offers the chance to link abnormalities in the B‐cell antibody repertoire to specific genomic variants and polymorphisms. Here, we discuss the current research using B‐cell antibody repertoire sequencing in three polygenic autoimmune diseases where there is good evidence for a pathological role for B‐cells, namely systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. These autoimmune diseases exhibit significantly skewed B‐cell receptor repertoires compared with healthy controls. Interestingly, some common repertoire defects are shared between diseases, such as elevated IGHV4‐34 gene usage. B‐cell clones have effectively been characterized and tracked between different tissues and blood in autoimmune disease. It has been hypothesized that these differences may signify differences in B‐cell tolerance; however, the mechanisms and implications of these defects are not clear. [ABSTRACT FROM AUTHOR]

Psychotic disorders are common and disabling. Overlaps in clinical course in addition to epidemiological and genetic associations raise the possibility that autoimmune mechanisms may underlie some psychoses, potentially offering novel therapeutic approaches. Several immune loci including the major histocompatibility complex and B-cell markers CD19 and CD20 achieve genome-wide significance in schizophrenia. Emerging evidence suggests a potential role via neurodevelopment in addition to classical immune pathways. Additionally, lymphocyte biology is increasingly investigated. Some reports note raised peripheral CD19+ and reduced CD3+ lymphocyte counts, with altered CD4 : CD8 ratios in acute psychosis. Also, post-mortem studies have found CD3+ and CD20+ lymphocyte infiltration in brain regions that are of functional relevance to psychosis. More specifically, the recent paradigm of neuronal surface antibody-mediated ( NSAb) central nervous system disease provides an antigen-specific model linking adaptive autoimmunity to psychopathology. NSAbs bind extracellular epitopes of signalling molecules that are classically implicated in psychosis such as NMDA and GABA receptors. This interaction may cause circuit dysfunction leading to psychosis among other neurological features in patients with autoimmune encephalitis. The detection of these cases is crucial as autoimmune encephalitis is ameliorated by commonly available immunotherapies. Meanwhile, the prevalence and relevance of these antibodies in people with isolated psychotic disorders is an area of emerging scientific and clinical interest. Collaborative efforts to achieve larger sample sizes, comparison of assay platforms, and placebo-controlled randomized clinical trials are now needed to establish an autoimmune contribution to psychosis. [ABSTRACT FROM AUTHOR]

The variable region of murine immunoglobulin heavy chain (Igh) is assembled by sequential DH- JH and VH- DJH recombination. The accessibility of the Igh locus determines the order of rearrangement. Because of the large number of VH genes and the lack of a suitable model, the epigenetic modifications of VH genes after DJH recombination have not previously been characterized. Here, we employed two v-Abl pro-B cell lines, in which the Igh locus is in germline and DJH-recombined configurations, respectively. The DJH junction displays the characteristics of a recombination centre, such as high levels of activation-associated histone modifications and recombination-activating gene protein ( RAG) binding in DJH-rearranged pro-B cells, which extend the recombination centre model proposed for the germline Igh locus. The different domains of the VH region have distinct epigenetic characteristics after DJH recombination. Distal VH genes have higher levels of active histone modifications, germline transcription and Pax5 binding, and good quality recombination signal sequences. Proximal VH genes are relatively close to the DJH recombination centre, which partially compensates for the low levels of the above active epigenetic modifications. DJH recombination centre might serve as a cis-acting element to regulate the accessibility of the VH region. Furthermore, we demonstrate that RAG weakly binds to functional VH genes, which is the first detailed assessment of RAG dynamic binding to VH genes. We provide a way for VH- DJH recombination in which the VH gene is brought into close proximity with the DJH recombination centre for RAG binding by a Pax5-dependent chromosomal compaction event, and held in this position for subsequent cleavage and VH- DJH joining. [ABSTRACT FROM AUTHOR]

Mucosal-associated invariant T ( MAIT) cells are conserved T cells that express a semi-invariant T-cell receptor (V α7.2 in humans and V α19 in mice). The development of MAIT cells requires the antigen-presenting MHC-related protein 1 ( MR1), as well as commensal bacteria. The mechanisms that regulate the functional expression of MR1 molecules and their loading with bacterial antigen in antigen-presenting cells are largely unknown. We have found that treating B cells with the Toll-like receptor 9 ( TLR9) agonist CpG increases MR1 surface expression. Interestingly, activation of TLR9 by CpG-A (but not CpG-B) enhances MR1 surface expression. This is limited to B cells and not other types of cells such as monocytes, T or natural killer cells. Knocking-down TLR9 expression by short hairpin RNA reduces MR1 surface expression and MR1-mediated bacterial antigen presentation. CpG-A triggers early endosomal TLR9 activation, whereas CpG-B is responsible for late endosomal/lysosomal activation of TLR9. Consistently, blocking endoplasmic reticulum to Golgi protein transport, rather than lysosomal acidification, suppressed MR1 antigen presentation. Overall, our results indicate that early endosomal TLR9 activation is important for MR1-mediated bacterial antigen presentation. [ABSTRACT FROM AUTHOR]

Burkholderia pseudomallei is the causative agent of melioidosis, an infectious disease with high incidence and mortality in South East Asia and northern Australia. To date there is no protective vaccine and antibiotic treatment is prolonged and not always effective. Most people living in endemic areas have been exposed to the bacteria and have developed some immunity, which may have helped to prevent disease. Here, we used a humanized mouse model (hu- PBL- SCID), reconstituted with human peripheral blood mononuclear cells from seropositive donors, to illustrate the potential of three known antigens (FliC, OmpA and N-PilO2) for boosting both T-cell and B-cell immune responses. All three antigens boosted the production of specific antibodies in vivo, and increased the number of antibody and interferon- γ-secreting cells, and induced antibody affinity maturation. Moreover, antigen-specific antibodies isolated from either seropositive individuals or boosted mice, were found to enhance phagocytosis and oxidative burst activities from human polymorphonuclear cells. Our study demonstrates that FliC, OmpA and N-PilO2 can stimulate human memory T and B cells and highlight the potential of the hu- PBL- SCID system for screening and evaluation of novel protein antigens for inclusion in future vaccine trials against melioidosis. [ABSTRACT FROM AUTHOR]

Vitamin A is an essential anti-infective agent with pleiotropic effects on cells of the immune system. The goal of the present study was to unravel the impact of the vitamin A metabolite retinoic acid (RA) on B-cell survival related both to normal B-cell homeostasis and to the detrimental effects imposed by DNA-damaging agents. By combining RA with Tolllike receptor 9 (TLR9) ligands, we show that RA prevents spontaneous, irradiation- and doxorubicin-induced apoptosis of human B cells in an RA receptor-dependent manner. RA-mediated survival involved up-regulation of the anti-apoptotic protein myeloid cell leukemia 1 (MCL1) at the transcriptional level, and knock down of MCL1 by small interfering RNA partially reversed the effects of RA. To ensure that the combination of TLR9-ligands and RA would not promote the survival of malignant B cells, the combined effects of stimulation with RA and TLR9 ligands was assessed on cells from patients with B-cell malignancies. In contrast to the effects on normal B cells, the combination of TLR9 stimulation and RA neither enhanced the MCL1 levels nor inhibited the death of malignant B cells challenged by DNA-damaging agents. Taken together, the present results reveal a vital role of MCL1 in RA-mediated survival of normal B cells. Moreover, the findings suggest that RA in combination with TLR9 ligands might be useful adjuvants in the treatment of B-cell malignancies by selectively protecting normal and not malignant B cells from DNAdamage- induced cell death. [ABSTRACT FROM AUTHOR]

CD38 is a 45 000 molecular weight transmembrane protein that is expressed in immature and mature lymphocytes. However, the expression and function of CD38 during B-cell differentiation in mice is poorly understood. Here, we report that CD38 is expressed from the earliest stages of B-cell development. Pre-pro- B, pro- B, pre- B and immature B cells from murine bone marrow all stained positive for CD38. Interestingly, CD38 expression increases with B-cell maturation. To assess the role of CD38 during B-cell maturation, CD38-deficient mice were analysed. CD38−/− mice showed a significant increase in both the frequency of B-lineage cells and the absolute numbers of pre-pro- B cells in bone marrow; however, no other differences were observed at later stages. CD38 cross-linking in Ba/ F3 cells promoted apoptosis and marked extracellular signal-regulated kinase ( ERK) phosphorylation, and these effects were reduced by treatment with the mitogen-activated protein kinase/ ERK kinase inhibitor PD98059, and similar effects were observed in B-cell precursors from bone marrow. These data demonstrate that B-cell precursors in mouse bone marrow express functional CD38 and implicate the early ligation of CD38 in the ERK-associated regulation of the B-lineage differentiation pathway. [ABSTRACT FROM AUTHOR]