Characterization of amoxicillin‐ and clavulanic acid‐specific T cells in patients with amoxicillin‐clavulanate–induced liver injury

Drug‐induced liver injury (DILI) frequently has a delayed onset with several human leukocyte antigen (HLA) genotypes affecting susceptibility, indicating a potential role for the adaptive immune system in the disease. The aim of this study was to investigate whether drug‐responsive T lymphocytes are detectable in patients who developed DILI with the combination, antimicrobial amoxicillin‐clavulanate. Lymphocytes from 6 of 7 patients were found to proliferate and/or secrete interferon‐gamma (IFN‐γ) when cultured with amoxicillin and/or clavulanic acid. Amoxicillin (n = 105) and clavulanic acid (n = 16) responsive CD4+ and CD8+ T‐cell clones expressing CCR, chemokine (C‐C motif) receptor 4, CCR9, and chemokine (C‐X‐C motif) receptor 3 were generated from patients with and without HLA risk alleles; no cross‐reactivity was observed between the two drug antigens. Amoxicillin clones were found to secrete a heterogeneous panel of mediators, including IFN‐γ, interleukin‐22 and cytolytic molecules. In contrast, cytokine secretion by the clavulanic acid clones was more restricted. CD4+ and CD8+ clones were major histocompatability complex class II and I restricted, respectively, with the drug antigen being presented to CD4+ clones in the context of HLA‐DR molecules. Several pieces of evidence indicate that the clones were activated by a hapten mechanism: First, professional antigen‐presenting cells (APCs) were required for optimal activation; second, pulsing APCs for 4‐16 hours activated the clones; and third, inhibition of processing abrogated the proliferative response and cytokine release. Conclusion: Both amoxicillin‐ and clavulanic acid–specific T cells participate in the liver injury that develops in certain patients exposed to amoxicillin‐clavulanate. (Hepatology 2015;62:887‐899

Antitumor effector B cells directly kill tumor cells via the Fas/FasL pathway and are regulated by IL‐10

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111143/1/eji3242.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/111143/2/eji3242-sup-0001-PRC.pd

NFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells

Epicutaneous application of Aldara cream containing the TLR7 agonist imiquimod (IMQ) to mice induces skin inflammation that exhibits many aspects of psoriasis, an inflammatory human skin disease. Here we show that mice depleted of B cells or bearing interleukin (IL)-10-deficient B cells show a fulminant inflammation upon IMQ exposure, whereas ablation of NFATc1 in B cells results in a suppression of Aldara-induced inflammation. In vitro, IMQ induces the proliferation and IL-10 expression by B cells that is blocked by BCR signals inducing NFATc1. By binding to HDAC1, a transcriptional repressor, and to an intronic site of the Il10 gene, NFATc1 suppresses IL-10 expression that dampens the production of tumour necrosis factor-α and IL-17 by T cells. These data indicate a close link between NFATc1 and IL-10 expression in B cells and suggest NFATc1 and, in particular, its inducible short isoform, NFATc1/αA, as a potential target to treat human psoriasis

Beneficial autoimmunity at body surfaces – immune surveillance and rapid type 2 immunity regulate tissue homeostasis and cancer

Epithelial cells line body surface tissues and provide a physicochemical barrier to the external environment. Frequent microbial and non-microbial challenges such as those imposed by mechanical disruption, injury or exposure to noxious environmental substances including chemicals, carcinogens, ultraviolet-irradiation or toxins cause activation of epithelial cells with release of cytokines and chemokines as well as alterations in the expression of cell surface ligands. Such display of epithelial stress is rapidly sensed by tissue resident immunocytes, which can directly interact with self-moieties on epithelial cells and initiate both local and systemic immune responses. Epithelial cells are thus key drivers of immune surveillance at body surface tissues. However, epithelial cells have a propensity to drive type 2 immunity (rather than type 1) upon non-invasive challenge or stress – a type of immunity whose regulation and function still remain enigmatic. Here we review the induction and possible role of type 2 immunity in epithelial tissues and propose that rapid immune surveillance and type 2 immunity are key regulators of tissue homeostasis and carcinogenesis

Exacerbated experimental arthritis in Wiskott–Aldrich syndrome protein deficiency: Modulatory role of regulatory B cells

Patients deficient in the cytoskeletal regulator Wiskott–Aldrich syndrome protein (WASp) are predisposed to varied autoimmunity, suggesting it has an important controlling role in participating cells. IL-10-producing regulatory B (Breg) cells are emerging as important mediators of immunosuppressive activity. In experimental, antigen-induced arthritis WASp-deficient (WASp knockout [WAS KO]) mice developed exacerbated disease associated with decreased Breg cells and regulatory T (Treg) cells, but increased Th17 cells in knee-draining LNs. Arthritic WAS KO mice showed increased serum levels of B-cell-activating factor, while their B cells were unresponsive in terms of B-cell-activating factor induced survival and IL-10 production. Adoptive transfer of WT Breg cells ameliorated arthritis in WAS KO recipients and restored a normal balance of Treg and Th17 cells. Mice with B-cell-restricted WASp deficiency, however, did not develop exacerbated arthritis, despite exhibiting reduced Breg- and Treg-cell numbers during active disease, and Th17 cells were not increased over equivalent WT levels. These findings support a contributory role for defective Breg cells in the development of WAS-related autoimmunity, but demonstrate that functional competence in other regulatory populations can be compensatory. A properly regulated cytoskeleton is therefore important for normal Breg-cell activity and complementation of defects in this lineage is likely to have important therapeutic benefits

Regulatory B cells in pregnancy: lessons from autoimmunity, graft tolerance, and cancer

The success of pregnancy is contingent on the maternal immune system recognizing and accommodating a growing semi-allogeneic fetus. Specialized subsets of lymphocytes capable of negative regulation are fundamental in this process, and include the regulatory T cells (Tregs) and potentially, regulatory B cells (Bregs). Most of our current understanding of the immune regulatory role of Bregs comes from studies in the fields of autoimmunity, transplantation tolerance, and cancer biology. Bregs control autoimmune diseases and can elicit graft tolerance by inhibiting the differentiation of effector T cells and dendritic cells (DCs), and activating Tregs. Furthermore, in cancer, Bregs are hijacked by neoplastic cells to promote tumorigenesis. Pregnancy therefore represents a condition that reconciles these fields-mechanisms must be in place to ensure maternal immunological tolerance throughout gravidity to allow the semi-allogeneic fetus to grow within. Thus, the mechanisms underlying Breg activities in autoimmune diseases, transplantation tolerance, and cancer may take place during pregnancy as well. In this review, we discuss the potential role of Bregs as guardians of pregnancy and propose an endocrine-modulated feedback loop highlighting the Breg-Treg-tolerogenic DC interface essential for the induction of maternal immune tolerance.Ruth Marian Guzman-Genuino and Kerrilyn R. Diene

B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6–producing B cells

B cells have paradoxical roles in autoimmunity, exerting both pathogenic and protective effects. Pathogenesis may be antibody independent, as B cell depletion therapy (BCDT) leads to amelioration of disease irrespective of autoantibody ablation. However, the mechanisms of pathogenesis are poorly understood. We demonstrate that BCDT alleviates central nervous system autoimmunity through ablation of IL-6–secreting pathogenic B cells. B cells from mice with experimental autoimmune encephalomyelitis (EAE) secreted elevated levels of IL-6 compared with B cells from naive controls, and mice with a B cell–specific IL-6 deficiency showed less severe disease than mice with wild-type B cells. Moreover, BCDT ameliorated EAE only in mice with IL-6–sufficient B cells. This mechanism of pathogenesis may also operate in multiple sclerosis (MS) because B cells from MS patients produced more IL-6 than B cells from healthy controls, and this abnormality was normalized with B cell reconstitution after Rituximab treatment. This suggests that BCDT improved disease progression, at least partly, by eliminating IL-6–producing B cells in MS patients. Taking these data together, we conclude that IL-6 secretion is a major mechanism of B cell–driven pathogenesis in T cell–mediated autoimmune disease such as EAE and MS

Revisiting the B-cell compartment in mouse and humans: more than one B-cell subset exists in the marginal zone and beyond.

International audienceABSTRACT: The immunological roles of B-cells are being revealed as increasingly complex by functions that are largely beyond their commitment to differentiate into plasma cells and produce antibodies, the key molecular protagonists of innate immunity, and also by their compartmentalisation, a more recently acknowledged property of this immune cell category. For decades, B-cells have been recognised by their expression of an immunoglobulin that serves the function of an antigen receptor, which mediates intracellular signalling assisted by companion molecules. As such, B-cells were considered simple in their functioning compared to the other major type of immune cell, the T-lymphocytes, which comprise conventional T-lymphocyte subsets with seminal roles in homeostasis and pathology, and non-conventional T-lymphocyte subsets for which increasing knowledge is accumulating. Since the discovery that the B-cell family included two distinct categories - the non-conventional, or extrafollicular, B1 cells, that have mainly been characterised in the mouse; and the conventional, or lymph node type, B2 cells - plus the detailed description of the main B-cell regulator, FcγRIIb, and the function of CD40+ antigen presenting cells as committed/memory B-cells, progress in B-cell physiology has been slower than in other areas of immunology. Cellular and molecular tools have enabled the revival of innate immunity by allowing almost all aspects of cellular immunology to be re-visited. As such, B-cells were found to express "Pathogen Recognition Receptors" such as TLRs, and use them in concert with B-cell signalling during innate and adaptive immunity. An era of B-cell phenotypic and functional analysis thus began that encompassed the study of B-cell microanatomy principally in the lymph nodes, spleen and mucosae. The novel discovery of the differential localisation of B-cells with distinct phenotypes and functions revealed the compartmentalisation of B-cells. This review thus aims to describe novel findings regarding the B-cell compartments found in the mouse as a model organism, and in human physiology and pathology. It must be emphasised that some differences are noticeable between the mouse and human systems, thus increasing the complexity of B-cell compartmentalisation. Special attention will be given to the (lymph node and spleen) marginal zones, which represent major crossroads for B-cell types and functions and a challenge for understanding better the role of B-cell specificities in innate and adaptive immunology

What\u27s new in online news?

This paper examines aspects of the field of Information Systems (IS) concerned with its diversity and with the rapid changes within the discipline that have been incurred by the continued evolution of the IS artefact. This examination is done in order to establish the suitability of the Cynefin framework, developed for knowledge management, as a suitable tool for sense-making in IS. A description and assessment of the Cynefin framework is provided with its varied applications in both organisational practice and research. The paper then applies the framework to make sense of some historical trends and contemporary issues of IS emphasising their diversity and changing nature. We conclude with speculation on how this approach may help guide future sense-making in IS research

Continuous Flow Synthesis of ZSM-5 Zeolite on the Order of Seconds

Zeolites have typically been synthesized via hydrothermal treatment, a process designed to artificially mimic the geological formation conditions of natural zeolites. This synthesis route, typically carried out in batch reactors like autoclaves, takes a time so long (typically, on the order of days) that the crystallization of zeolites had long been believed to be very slow in nature. Long periods of hydrothermal treatment also cause a burden on both energy efficiency and operational costs. Recently, we have reported the ultrafast syntheses of a class of industrially important zeolites within several minutes.[1,2] Further shortening the crystallization time to the order of seconds would be a great challenge but can significantly benefit the mass product of zeolites as well as the fundamental understanding of the crystallization mechanism