Clinical & Experimental Immunology

Cover image for Vol. 191 Issue 2

Edited By: Leonie Taams

Impact Factor: 3.41

ISI Journal Citation Reports © Ranking: 2016: 62/151 (Immunology)

Online ISSN: 1365-2249

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  • Immune checkpoint inhibitors: new strategies to checkmate cancer

    Immune checkpoint inhibitors: new strategies to checkmate cancer

    Immune checkpoint inhibitor (ICI) blockade reverses tumour-mediated immune suppression. (a) Established tumours block immune attack through a variety of mechanisms, including inhibition of tumour-specific cytotoxic T lymphocyte (CTL) and CD4 T cell activation and function (1). This is driven by tumour over-expression of programmed cell death protein 1(PD-L1), interacting with tumour-specific T cell PD-1 receptor (2) and T cell anergy induced by tumour-mediated T cell expression of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitory receptor (4). In addition, tolerogenic dendritic cells (DC) drive regulatory T cell (Treg) induction and expansion via CTLA-4 (3) and accumulation of Tregs then contributes to the immunosuppressive milieu of the tumour microenvironment (TME). (b) After ICI therapy, there is re-activation and proliferation of tumour-specific CTLs via blockade of the PD-1 axis (1), and return of functional cytotoxicity, resulting in perforin release and tumour cell killing (2). As tumour damage increases, the TME is disrupted allowing macrophages to deplete Tregs via fragment crystalline receptor (FcR) binding of anti-CTLA-4 antibody (3). Tumour antigen release is driven by immune lysis of tumour cells which are processed by conventional DC and presented to naive T cells in context of checkpoint inhibition of CTLA-4, enhancing CTL proliferation and function (4). Tumour damage and antigen release is also supplemented by concomitant use of conventional chemo/radiotherapy, which can reveal new tumour-associated antigens and contribute to anti-tumour immune responses (5).

  • Ovarian cancer stem cells promote tumour immune privilege and invasion via CCL5 and regulatory T cells

    Ovarian cancer stem cells promote tumour immune privilege and invasion via CCL5 and regulatory T cells

    Schematic representation of the relationship between cancer stem-like cells and regulatory T cells (Tregs). (a,b) Ovarian cancer stem cells (CSCs) affected immune tolerance by recruiting more Tregs to the tumour microenvironment than did non-CSCs, due to their high expression of C-C motif chemokine ligand 5 (CCL5) and the high expression of CCR5 on the Tregs of ovarian cancer patients. The Tregs infiltrated the microenvironment enriched in ovarian CSCs and secreted high levels of interleukin (IL)-10 to inhibit anti-tumour immunity. Ovarian cancer cells (Ca) promoted Tregs to express MMP9, which can degrade the extracellular matrix (ECM) and lead to the invasion of tumour cells.

  • C4B gene influences intestinal microbiota through complement activation in patients with paediatric-onset inflammatory bowel disease

    C4B gene influences intestinal microbiota through complement activation in patients with paediatric-onset inflammatory bowel disease

    A schematic presentation of the influence of C4B gene number on host immune functions and microbiota in paediatric inflammatory bowel disease. (a) The complement system can be initiated in three distinct ways: the classical, the lectin or the alternative pathway. (b) These pathways merge to activate C3 to C3a and C3b and continue as a common terminal pathway. (c) If the complement system is activated fully it leads to the removal of bacteria through bacteriolysis by the membrane attack complex or phagocytosis of C3b/iC3b-opsonized bacteria by neutrophils or macrophages. The genetically normal situation with the presence of one to two C4B genes in children with inflammatory bowel disease (IBD) in this study is linked to a stronger complement activation, intestinal inflammation and lower diversity in microbiota. Patients without C4B genes have less complement activation, intestinal inflammation and healthier type microbiota. Thereby, they seem to be protected from the inflammatory state and disturbed microbiota. C4 is shown in red. Complement activation was measured from bacteria-stimulated IBD patient serum by analysing C3a and soluble terminal complement complex (SC5b-9) levels (shown in green). C3a = C3 activation product, an anaphylatoxin; C4 = complement component 4; TCC = terminal complement complex including complement proteins C5b–C9. TCC indicates both the soluble form (SC5b-9) and the complement membrane attack complex (MAC).

  • Redundant and regulatory roles for Toll-like receptors in Leishmania infection

    Redundant and regulatory roles for Toll-like receptors in Leishmania infection

    Leishmania-macrophage interaction: Leishmania–macrophage interaction begins at the site of infection. Promastigotes engage in various receptor-mediated internalization processes minimally sensitizing the microbicidal functions. Leishmanial gp63 and lipophosphoglycan (LPG) are major antigens that interact with macrophage-expressed fibronectin receptor (FnR), complement receptor 3 (CR3) and mannose fucose receptor (MFR) either actively or passively after binding to opsonins C3 and C-reactive protein (CRP). LPG and gp63 are the two major factors responsible for leishmanial virulence. gp63 brings out the cleavage of opsonin C3b to inactive C3bi that facilitates promastigote uptake by interacting with CR3 receptor. Fcγ receptor (FcγR)-mediated recognition of immunoglobulin (IgG)-covered leishmanial surface antigens results in extracellular regulated kinase (ERK)-mediated production of interleukin (IL)-10, an anti-inflammatory cytokine that suppresses the microbicidal activity of macrophages. gp63 is also implicated in directly activating SRC homology region-2 domain containing phosphatase-1 (SHP-1) phosphatase, which inhibits mitogen-activated protein kinase (MAPK) signalling and cytokine production. LPG is also involved in the modulation of protein kinase C (PKC) and MAPK signalling.

  • Immune deficiency and autoimmunity in patients with CTLA-4 (CD152) mutations

    Immune deficiency and autoimmunity in patients with CTLA-4 (CD152) mutations

    Schematic view of reported cytotoxic T lymphocyte antigen-4 (CTLA-4) mutations. DNA mutations are shown in the upper half of the diagram and aligned with amino acid changes below. The alignment between exons and protein functional domains is shown. Mutations are colour-coded according to the report in which they are described.

  • T helper type 1-related molecules as well as interleukin-15 are hyperexpressed in the skin lesions of patients with pyoderma gangrenosum

    T helper type 1-related molecules as well as interleukin-15 are hyperexpressed in the skin lesions of patients with pyoderma gangrenosum

    Immunohistochemical staining for the T helper 1-associated markers interleukin (IL)-12, interferon (IFN)-γ and the chemokine receptors C-X-C motif chemokine receptor 3 (CXCR3) and C-C motif chemokine receptor 5 (CCR5) in skin biopsy specimens from patients with pyoderma gangrenosum (PG), Sweet syndrome (SS) and healthy controls (HC). Magnification: ×200.

  • Transplantation tolerance: don't forget about the B cells

    Transplantation tolerance: don't forget about the B cells

    Fate of B cells in rejection and tolerance. The activation and differentiation of naive alloreative B cells during rejection occurs in a T cell- and germinal centre-dependent manner. Under tolerogenic conditions, naive alloreactive B cells encounter antigen, but in the absence of T cell help may be deleted, develop into regulatory B cells (Bregs)/B10 cells that suppress T cell responses, and into anergic or suppressed B cells that fail to develop into antibody-secreting plasma cells.

  • The role of stromal cells in inflammatory bone loss

    The role of stromal cells in inflammatory bone loss

    The role of fibroblast-like synoviocytes (FLS) in inflammatory bone destruction. Under healthy conditions, there is a balance between bone formation and bone destruction to replace old bone tisssue and to repair bone defects. In rheumatoid arthritis (RA), more bone is degraded by osteoclasts than is created by osteoblasts, shifting the balance towards bone destruction. During inflammation, stromal FLS, located in the synovial membrane of the joint space, are able to influence this balance directly or indirectly. FLS release receptor-activator of nuclear factor-kappa B (RANKL) in response to inflammatory cytokines such as tumour necrosis factor (TNF)-α, which subsequently stimulates osteoclastogenesis directly. They also communicate with T cells or release inhibitors of bone formation, such as sclerostin and Dickkopf-1 (DKK1). In contrast to DKK1, sclerostin not only blocks osteoblast differentiation but also inhibits specifically TNF-mediated bone destruction, suggesting a protective effect in TNF-mediated bone loss. Other factors released by FLS, such as myostatin, activates bone destruction directly. Different subsets of FLS, especially gp38+ and FAP+-expressing FLS, are highly migratory and invasive and seem to be important for cartilage and bone destruction.

  • The role of genomics in common variable immunodeficiency disorders

    The role of genomics in common variable immunodeficiency disorders

    There are multiple genetic components involved in common variable immunodeficiency disorder (CVID) pathogenesis. Monogenic causes of CVID has been found in approximately 10% of cases, and primarily modify molecules associated with the B cell receptor complex. In most cases there is a polygenic mode of inheritance, whereby variants in multiple genes can contribute to the same or diverse phenotypes. Further genetic complexity may come from transcriptional and epigenetic disturbances.

  • Production of complement components by cells of the immune system

    Production of complement components by cells of the immune system

    Schematic representation of the complement system. The complement system can be activated via three different pathways: the classical pathway (CP), the lectin pathway (LP) and the alternative pathway (AP). These pathways have their own sequential manner in forming a C3 convertase: C4b2a or C3bBb. These C3 convertases cleave the central component C3 generating two activation fragments, C3a and C3b. The C3a is able to bind its anaphylatoxin receptor the C3aR, whereas C3b can opsonize a target membrane. C3b and its further degradation products, iC3b, C3c and C3d/C3dg are able to bind various complement receptors (CRs). Additionally, C3b can bind to the former C3 convertase which then results in formation of the C5 convertase: C4bC2aC3b or C3bBbC3b. The C5 convertase cleaves C5 in two activation fragments C5a and C5b. C5a can bind to its anaphylatoxin receptors C5aR1 and C5aR2, whereas C5b marks the start of the formation of the membrane attack complex (MAC). In a sequential manner C5b, C6, C7, C8 and up to 16 molecules of C9 bind together to form a MAC. Various inhibitors of this system are marked in pink boxes. MBL = mannose binding lectin; MASP = MBL-associated serine protease; FB = factor B; FP = factor P; FD = factor D; FH = factor H; C1INH = C1 inhibitor; FI = factor I (FI), C4BP = C4b-binding protein; CR = complement receptor.

  • Tumour-activated liver stromal cells regulate myeloid-derived suppressor cells accumulation in the liver

    Tumour‐activated liver stromal cells regulate myeloid‐derived suppressor cells accumulation in the liver

    Liver stromal cells promote myeloid-derived suppressor cells (MDSCs) accumulation in the liver and at the tumour site. (a) 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide (DiR)-labelled MDSCs were transferred intravenously (i.v.) (5 × 106 cells per mouse) to recipient mice as indicated (n = 4) and were imaged 3 h later. (b) Tumour nodules from the two groups of tumour-bearing mice were isolated and imaged 3 h after cell transfer. (c) The fold-changes in liver and tumour photo counts in the two groups of tumour-bearing mice. (d) Tumour volumes from the groups of tumour-bearing mice are shown (n = 6 per group). The experiments were repeated three times. * P < 0·05. Student's t-test.

  • Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels

    Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels

    A conceptual natural killer (NK) model for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) patients. Pregnenolone sulphate (PregS) is a potent steroid that activated transient receptor potential melastatin 3 ion channels (TRPM3) on NK cell subsets. PregS in combination with thapsigargin elevated cytoplasmic calcium and is suggested to phosphorylate extracellular-regulated kinase (ERK) 1/2 and polarization of secretory granules for degranulation in CD56dimCD16+ NK cells, resulting in target K562 cell death, whereas PregS-stimulated CD56brightCD16dim/– NK cells may activate p38 MAPK signalling pathways involved in the nuclear factor kappa B (NF-κβ) inflammatory immune response.

  • Immune checkpoint inhibitors: new strategies to checkmate cancer
  • Ovarian cancer stem cells promote tumour immune privilege and invasion via CCL5 and regulatory T cells
  • C4B gene influences intestinal microbiota through complement activation in patients with paediatric-onset inflammatory bowel disease
  • Redundant and regulatory roles for Toll-like receptors in Leishmania infection
  • Immune deficiency and autoimmunity in patients with CTLA-4 (CD152) mutations
  • T helper type 1-related molecules as well as interleukin-15 are hyperexpressed in the skin lesions of patients with pyoderma gangrenosum
  • Transplantation tolerance: don't forget about the B cells
  • The role of stromal cells in inflammatory bone loss
  • The role of genomics in common variable immunodeficiency disorders
  • Production of complement components by cells of the immune system
  • Tumour‐activated liver stromal cells regulate myeloid‐derived suppressor cells accumulation in the liver
  • Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels

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About Clinical & Experimental Immunology

Clinical & Experimental Immunology (CEI) is an international, authoritative, timely and impactful resource of clinical and translational research articles, reviews, and opinion pieces that further our understanding of the immunology of human disease. CEI also aims to promote and advance best practice in clinical immunology.

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The British Society for Immunology is delighted to announce Leonie Taams as the new Editor-in-Chief of Clinical & Experimental Immunology. Leonie is Professor of Immune Regulation and Inflammation at King’s College London, and takes over from Mark Peakman. Mark oversaw a period of growth in his two terms as EiC and the BSI would like to express their gratitude to him for his outstanding contribution to the journal.

Leonie Taams

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