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  • SLAMF receptors on normal and malignant B cells
    Clin. Immunol. (IF 3.557) Pub Date : 2018-11-15
    Idit Shachar, Avital Barak, Hadas Lewinsky, Lital Sever, Lihi Radomir

    The Signaling Lymphocyte Activation Molecule family (SLAMF) is a collection of nine surface receptors expressed mainly on hematopoietic cells, and was found to modulate the behavior of immune cells. SLAMF receptors are expressed on B cells in health and disease. Each SLAM receptor has a unique differential expression pattern during the development and activation of B cells. Furthermore, recent findings have revealed a principal role for this family of receptors in B cell malignancies, emphasizing their importance in the control of malignant cell survival, cell to cell communication within the tumor microenvironment, retention in the supporting niches and regulation of T cell anti-tumor response. This review summarizes the latest studies regarding SLAMF expression and behavior in B cells and in B cell pathologies, and discusses the therapeutic potential of these receptors.

    更新日期:2018-11-15
  • Association of anti-nuclear matrix protein 2 antibody with complications in patients with idiopathic inflammatory myopathies: A meta-analysis of 20 cohorts
    Clin. Immunol. (IF 3.557) Pub Date : 2018-11-13
    Linqing Zhong, Zhongxun Yu, Hongmei Song

    BackgroundSeveral complications like calcinosis, interstitial lung disease (ILD) or malignancy, are primary causes leading to poor outcomes in idiopathic inflammatory myopathies (IIM) patients. Specific antibodies might help to indicate the occurrence or absence of these complications.ObjectiveThe aim of this study was to evaluate the association of anti-nuclear matrix protein 2 antibody (anti-NXP2) with calcinosis, ILD and malignancy in IIM patients.MethodsTwo investigators independently searched literature about the relation of anti-NXP2 with calcinosis, ILD, malignancy in IIM patients in PubMed, EMBASE, Web of Science databases, then selected eligible articles and extracted data from the included studies. The association between anti-NXP2 and these complications was assessed by odds ratios (OR) and 95% confidence intervals (95% CI). Further quantitative meta-analysis, subgroup analysis, sensitivity analysis and publication bias analysis were conducted with STATA 14.0 software (Stata Corp.; College Station, Texas, USA). A fixed-effects model (the Mantel-Haenszel method) was employed when I2 < 25%, otherwise a random-effects model (the Mantel-Haenszel method) was used.ResultsTwenty cohorts with 3064 IIM patients were included in this meta-analysis, among which 9 were about calcinosis in adults, 6 about calcinosis in juvenile patients, 9 about ILD in adults, 3 about ILD in juvenile patients, while 13 about malignancy in adult patients. Anti-NXP2 was more common in patients with calcinosis than those without calcinosis (pooled OR = 4.00, 95% CI: 2.65–6.06 in adults; pooled OR = 1.62, 95% CI: 1.14–2.30 in juvenile patients). On the contrary, this antibody was less common in adult patients with ILD than those without ILD (pooled OR: 0.33, 95% CI: 0.19–0.56). No significant difference concerning the incidence of anti-NXP2 antibody was found in IIM patients between those with and without cancer (pooled OR = 1.42, 95% CI: 0.69–2.91).ConclusionThe present study indicates that anti-NXP2 autoantibody is a risk factor for development into calcinosis both in adult and juvenile patients, while a protective factor for ILD in adult patients. Anti-NXP2 had no relation with malignancy in adult patients.

    更新日期:2018-11-14
  • The hyper IgM syndromes: Epidemiology, pathogenesis, clinical manifestations, diagnosis and management
    Clin. Immunol. (IF 3.557) Pub Date : 2018-11-13
    Reza Yazdani, Saba Fekrvand, Sepideh Shahkarami, Gholamreza Azizi, Bobak Moazzami, Hassan Abolhassani, Asghar Aghamohammadi

    Hyper Immunoglobulin M syndrome (HIGM) is a rare primary immunodeficiency disorder characterized by low or absent levels of serum IgG, IgA, IgE and normal or increased levels of serum IgM. Various X-linked and autosomal recessive/dominant mutations have been reported as the underlying cause of the disease. Based on the underlying genetic defect, the affected patients present a variety of clinical manifestations including pulmonary and gastrointestinal complications, autoimmune disorders, hematologic abnormalities, lymphoproliferation and malignancies which could be controlled by multiple relevant therapeutic approaches. Herein, the epidemiology, pathogenesis, clinical manifestations, diagnosis, management, prognosis and treatment in patients with HIGM syndrome have been reviewed.

    更新日期:2018-11-14
  • New insights into immune cells cross-talk during IgG4-related disease
    Clin. Immunol. (IF 3.557) Pub Date : 2018-11-10
    Fahd Touzani, Agnieszka Pozdzik

    Immunoglobulin G4-related disease (IgG4-RD) is a newly acknowledged entity, characterized by an immune-mediated fibro-inflammatory process affecting virtually all organs, with infiltration of IgG4+ bearing plasma cells. Until today the pathogenesis of IgG4-RD remains unknown. Treatment with anti-CD20 monoclonal antibodies efficiently induced remission and attenuated the secretory phenotype of myofibroblasts responsible of uncontrolled collagen deposition. This supports the pathogenic role of the adaptive immunity, particularly B cell compartment and B cell/T cell interaction. Latest studies have also highlighted the importance of innate immune system that has been underestimated before and the key role of a specific T cell subset, T follicular helper cells that are involved in IgG4-class-switching and plasmablast differentiation. In this review, we aim to review the most recent knowledge of innate immunity, T and B cells involvement in IgG4-RD, and introduce tertiary lymphoid organs (TLO) as a potential marker of relapse in this condition.

    更新日期:2018-11-10
  • Signaling lymphocyte activation molecule family in systemic lupus erythematosus
    Clin. Immunol. (IF 3.557) Pub Date : 2018-11-08
    Denis Comte, Maria P. Karampetsou, Morgane Humbel, George C. Tsokos

    Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by a breakdown in immune tolerance leading to the development of auto-reactive lymphocytes and autoantibodies. Recent findings have provided new insight on the role of the signaling lymphocytic activation molecule family (SLAMF) receptors, a group of nine co-regulatory molecules involved in the activation of hematopoietic cells, and their downstream protein SLAM-associated protein (SAP), into the pathogenesis of SLE. This review summarizes the current knowledge on SLAMF in human SLE immunopathogenesis, and the importance of SLAMF molecules as new therapeutic targets.

    更新日期:2018-11-09
  • Natural and modified IL-2 for the treatment of cancer and autoimmune diseases
    Clin. Immunol. (IF 3.557) Pub Date : 2018-11-08
    Masayuki Mizui

    Interleukin-2 (IL-2) is a pleiotropic cytokine required for both effector lymphocyte proliferation/differentiation and regulatory T cell expansion/survival. Ability to receive IL-2 signals is defined by the affinity to distinct IL-2-receptor-complexes on each subset of cells. While IL-2 targets anti-tumor cytotoxic lymphocytes (CTLs) for the treatment of patients with melanoma or renal cell carcinoma, IL-2 directed at regulatory T (Treg) cells has value in several immune-related diseases including chronic graft-versus-host disease (cGVHD), type 1 diabetes (T1D) and systemic lupus erythematosus (SLE). A variety of IL-2 alteration has been made to deliver IL-2 to the proper target, including mutant IL-2, IL-2-fusion proteins and anti-IL-2 antibodies. Experimental and clinical trials with IL-2 are spreading for diverse group of diseases. Although the sustainability and efficiency of IL-2-responding cells in controlling disease activity are still not fully understood, the results of clinical trials will provide a basis of the most effective regimen for each disease.

    更新日期:2018-11-08
  • A Markov Multi-State model of lupus nephritis urine biomarker panel dynamics in children: Predicting changes in disease activity
    Clin. Immunol. (IF 3.557) Pub Date : 2018-11-02
    E.M.D. Smith, A. Eleuteri, B. Goilav, L. Lewandowski, A. Phuti, T. Rubinstein, D. Wahezi, C.A. Jones, S.D. Marks, R. Corkhill, C. Pilkington, K. Tullus, C. Putterman, C. Scott, A.C. Fisher, M.W. Beresford

    Background A urine ‘biomarker panel’ comprising alpha-1-acid-glycoprotein, ceruloplasmin, transferrin and lipocalin-like-prostaglandin-D synthase performs to an ‘excellent’ level for lupus nephritis identification in children cross-sectionally. The aim of this study was to assess if this biomarker panel predicts lupus nephritis flare/remission longitudinally. Methods The novel urinary biomarker panel was quantified by enzyme linked immunoabsorbant assay in participants of the United Kingdom Juvenile Systemic Lupus Erythematosus (UK JSLE) Cohort Study, the Einstein Lupus Cohort, and the South African Paediatric Lupus Cohort. Monocyte chemoattractant protein-1 and vascular cell adhesion molecule-1 were also quantified in view of evidence from other longitudinal studies. Serial urine samples were collected during routine care with detailed clinical and demographic data. A Markov Multi-State model of state transitions was fitted, with predictive clinical/biomarker factors assessed by a corrected Akaike Information Criterion (AICc) score (the better the model, the lower the AICc score). Results The study included 184 longitudinal observations from 80 patients. The homogeneous multi-state Markov model of lupus nephritis activity AICc score was 147.85. Alpha-1-acid-glycoprotein and ceruloplasmin were identified to be the best predictive factors, reducing the AICc score to 139.81 and 141.40 respectively. Ceruloplasmin was associated with the active-to-inactive transition (hazard ratio 0.60 (95% confidence interval [0.39, 0.93])), and alpha-1-acid-glycoprotein with the inactive-to-active transition (hazard ratio 1.49 (95% confidence interval [1.10, 2.02])). Inputting individual alpha-1-acid-glycoprotein/ceruloplasmin values provides 3, 6 and 12 months probabilities of state transition. Conclusions Alpha-1-acid-glycoprotein was predictive of active lupus nephritis flare, whereas ceruloplasmin was predictive of remission. The Markov state-space model warrants testing in a prospective clinical trial of lupus nephritis biomarker led monitoring.

    更新日期:2018-11-05
  • 2B4 dysfunction in XLP1 NK cells: More than inability to control EBV infection
    Clin. Immunol. (IF 3.557) Pub Date : 2018-11-02
    Daniela Pende, Raffaella Meazza, Stefania Marcenaro, Maurizio Aricò, Cristina Bottino

    X-linked lymphoproliferative disease 1 (XLP1) is a monogenic disorder caused by mutations in SH2D1A, resulting in the absence/dysfunction of the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). Consequently, SLAM receptors as 2B4 (CD244) and NTB-A (SLAMF6), upon ligand engagement, exert inhibitory instead of activating function. This causes an immune dysfunction that is worsened by the selective inability of NK and T cells to kill EBV-infected B cells with dramatic clinical sequelae (e.g. fulminant mononucleosis, hyperinflammation, lymphoma). Here we outline recent findings on the interplay between inhibitory 2B4 and the various activating receptors in NK cells. 2B4 engagement selectively blocks ITAM-dependent activating receptors as NCR and CD16, while it does not affect NKG2D and DNAM-1. Furthermore, inhibitory 2B4 participates to NK cell education, as highlighted by the existence in XLP1 patients of a large subset of fully functional NK cells that lack self-HLA specific inhibitory receptors and exert autoreactivity against mature dendritic cells.

    更新日期:2018-11-05
  • Clinical presentation, immunologic features, and hematopoietic stem cell transplant outcomes for IKBKB immune deficiency
    Clin. Immunol. (IF 3.557) Pub Date : 2018-10-31
    Geoffrey D.E. Cuvelier, Tamar S. Rubin, Anne Junker, Roona Sinha, Alan M. Rosenberg, Donna A. Wall, Marlis L. Schroeder

    IKBKB deficiency is a rare but life-threatening primary immunodeficiency disorder, involving activation defects in adaptive and innate immunity. We present sixteen cases of a homozygous IKBKB mutation (c.1292dupG) in infants characterized by early-onset bacterial, viral, fungal and Mycobacterial infections. In most cases, T- and B-cells were quantitatively normal, but phenotypically naïve, with severe hypogammaglobulinemia. T-cell receptor excision circles were normal, meaning newborn screening by TREC analysis would miss IKBKB cases. Although IKBKB deficiency does not meet traditional laboratory based definitions for SCID, this combined immune deficiency appears to be at least as profound. Urgent HSCT, performed in eight patients, remains the only known curative therapy, although only three patients are survivors. Ongoing infections after transplant remain a concern, and may be due to combinations of poor social determinants of health, secondary graft failure, and failure of HSCT to replace non-hematopoietic cells important in immune function and dependent upon IKK/NF-κB pathways.

    更新日期:2018-11-02
  • IVIG induces apoptotic cell death in CD56dim NK cells resulting in inhibition of ADCC effector activity of human PBMC
    Clin. Immunol. (IF 3.557) Pub Date : 2018-10-31
    Sebastian Bunk, Padmapriya Ponnuswamy, Azra Trbic, Mantas Malisauskas, Heinz Anderle, Alfred Weber, Josenato Ilas, Anna M. Winkler, H. Arno Butterweck, Wolfgang Teschner, Friedrich Scheiflinger, Corinna Hermann, Birgit M. Reipert

    The mechanism of the efficacy of Intravenous immunoglobulins (IVIG) in autoimmune and inflammatory diseases is not well understood. This study aimed at understanding mechanisms of IVIG-mediated suppression of effector cell activities of peripheral blood mononuclear cells (PBMC) in antibody-dependent cellular cytotoxicity (ADCC). We were particularly interested in CD56dim NK cells, the main ADCC effector cells in PBMC. Exposure of PBMC to IVIG for at least 48 h induced a caspase-3-dependent apoptotic cell death of CD56dim NK cells without affecting CD56bright NK cells. Induction of apoptosis in CD56dim NK cells and concomitant suppression of ADCC effector activities of PBMC was associated with the monomer fraction of IVIG. Moreover, it was independent of IgG sialyation, did not depend on engagement of FcγRIII and could not be mimicked by IVIG (Fab’)2 or IVIG Fc preparations. The described effect could contribute to the reduction of peripheral NK cells observed during IVIG therapy in patients.

    更新日期:2018-10-31
  • Targeting cytokines to treat autoinflammatory diseases
    Clin. Immunol. (IF 3.557) Pub Date : 2018-10-28
    Jonathan S. Hausmann

    Autoinflammatory diseases are rare group conditions manifested by recurrent fevers, systemic inflammation, and dysfunctions of the innate immune system. These conditions are characterized by overproduction or lack of inhibition of various cytokines, and the advent of biologic drugs that block specific cytokines involved in these conditions have revolutionized their treatment. In this review, I will discuss the most common autoinflammatory conditions of adulthood including Familial Mediterranean Fever, cryopyrin-associated periodic syndrome, mevalonate kinase deficiency/hyperimmunoglobulinemia D Syndrome, TNF receptor-associated autoinflammatory syndrome, and systemic juvenile idiopathic arthritis/adult-onset Still's disease. I will discuss how IL-1, IL-6, IL-18, and TNF play pathogenic roles in these conditions and will review the evidence behind cytokine blockade for these diseases. Throughout the paper, I will reflect on gaps in knowledge of autoinflammatory diseases and will highlight the latest advances and newest drugs in development.

    更新日期:2018-10-30
  • SLAMF1/CD150 in hematologic malignancies: Silent marker or active player?
    Clin. Immunol. (IF 3.557) Pub Date : 2018-10-25
    Inna Gordiienko, Larysa Shlapatska, Larysa Kovalevska, Svetlana P. Sidorenko

    SLAMF1/CD150 receptor is a founder of signaling lymphocyte activation molecule (SLAM) family of cell-surface receptors. It is widely expressed on cells within hematopoietic system. In hematologic malignancies CD150 cell surface expression is restricted to cutaneous T-cell lymphomas, few types of B-cell non-Hodgkin's lymphoma, near half of cases of chronic lymphocytic leukemia, Hodgkin's lymphoma, and multiple myeloma. Differential expression among various types of hematological malignancies allows considering CD150 as diagnostical and potential prognostic marker. Moreover, CD150 may be a target for antibody-based or measles virus oncolytic therapy. Due to CD150 signaling properties it is involved in regulation of malignant cell fate decision and tumor microenvironment in Hodgkin's lymphoma and chronic lymphocytic leukemia. This review summarizes evidence for the important role of CD150 in pathogenesis of hematologic malignancies.

    更新日期:2018-10-26
  • CD84 cell surface signaling molecule: An emerging biomarker and target for cancer and autoimmune disorders
    Clin. Immunol. (IF 3.557) Pub Date : 2018-10-26
    Marta Cuenca, Jordi Sintes, Árpád Lányi, Pablo Engel

    CD84 (SLAMF5) is a member of the SLAM family of cell-surface immunoreceptors. Broadly expressed on most immune cell subsets, CD84 functions as a homophilic adhesion molecule, whose signaling can activate or inhibit leukocyte function depending on the cell type and its stage of activation or differentiation. CD84-mediated signaling regulates diverse immunological processes, including T cell cytokine secretion, natural killer cell cytotoxicity, monocyte activation, autophagy, cognate T:B interactions, and B cell tolerance at the germinal center checkpoint. Recently, alterations in CD84 have been related to autoimmune and lymphoproliferative disorders. Specific allelic variations in CD84 are associated with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. In chronic lymphocytic leukemia, CD84 mediates intrinsic and stroma-induced survival of malignant cells. In this review, we describe our current understanding of the structure and function of CD84 and its potential role as a therapeutic target and biomarker in inflammatory autoimmune disorders and cancer.

    更新日期:2018-10-26
  • Hypogammaglobulinemia with decreased class-switched B-cells and dysregulated T-follicular-helper cells in IPEX syndrome
    Clin. Immunol. (IF 3.557) Pub Date : 2018-10-24
    Oded Shamriz, Kiran Patel, Rebecca A. Marsh, Jacob Bleesing, Avni Y. Joshi, Laura Lucas, Chengyu Prince, Bojana B. Pencheva, Lisa Kobrynski, Shanmuganathan Chandrakasan

    Early onset multisystem autoimmunity is commonly the defining feature of IPEX. Recurrent sinopulmonary infections and CVID-like phenotype were not previously recognized as a presentation in IPEX. Herein, we describe three extended family members with IPEX. In addition to autoimmunity, all three had a CVID-like presentation consisting of recurrent sinopulmonary infections, hypogammaglobulinemia and B-cell class switching defect. In vitro studies have shown that the B cell class switching defect is not B cell intrinsic. Additionally, a marked increase in circulating T follicular helper (cTFH) cells with high IFN-γ and IL-17 secretion on stimulation was noted in our patients. The dysregulated cTFH cells could contribute to a decreased B cell class switching. However, the exact mechanism of how expanded and dysregulated cTFH lead to B cell class switching defect and hypogammaglobulinemia in our patients is not clear. Our study could extend the clinical spectrum of IPEX to include a CVID-like presentation.

    更新日期:2018-10-25
  • 2B4 and CD48: A powerful couple of the immune system
    Clin. Immunol. (IF 3.557) Pub Date : 2018-10-24
    Hadas Pahima, Pier Giorgio Puzzovio, Francesca Levi-Schaffer

    The signaling lymphocytic activation molecule (SLAM) family of receptors (SLAMF) is a group of receptors belonging to the CD2 family. It is composed of several members expressed on many hematopoietic cells. Most of the receptors interact in a homophilic fashion with neighboring cells. Their distribution and binding properties, together with their ability to function as both activating and inhibitory receptors, put them as key players in the immune system regulation. Several SLAM family receptors have been extensively investigated. This review mainly focuses on CD244 (2B4 or SLAMF4,) and CD48, particularly as expressed by the key cells of allergy, mast cells and eosinophils.

    更新日期:2018-10-24
  • Imbalance of two main circulating dendritic cell subsets in patients with myasthenia gravis
    Clin. Immunol. (IF 3.557) Pub Date : 2018-10-22
    Pei Chen, Yingkai Li, Hao Huang, Yan Li, Zhenguang Chen, Xiaoxi Liu, Li Qiu, Changyi Ou, Zhidong Huang, Zhongqiang Lin, Hao Ran, Weibin Liu

    Although it is well documented that circulating dendritic cells (DCs) have specialized features in many kinds of physiological and pathological condition of human, there is still lack reports about the features of DCs in the peripheral blood of myasthenia gravis (MG) patients. We aimed to investigate the quantitative and component features of DCs and their implication in MG. We collected peripheral blood from different kinds of MG patients and recorded their clinical characteristics. Using flow cytometry, we distinguished circulating DC subsets [plasmacytoid DCs (pDCs) and myeloid DCs (mDCs)] and enumerated their densities in peripheral blood. Absolute numbers of circulating pDCs were significantly decreased in naïve MG patients compared with healthy controls, resulting in a markedly lower ratio of pDCs/mDCs (percentage). Thus, there was an imbalance in the proportions of different circulating DC subsets. We did not find clustered pDCs in the hyperplastic thymus of MG patients. The clinical status of MG patients was improved after drug treatment, together with an increased ratio of pDCs/mDCs. In a longitudinal follow-up, we observed that circulating mDCs were significantly reduced after 1 month of therapy with a steroid and immunosuppressant, resulting in recovery of the pDC/mDC ratio. The ratio of circulating DC subsets might reflect the balance between the autoimmune response and immune tolerance of a patient, and ratio changes during treatment could be a promising marker to predict the efficacy of a specific drug used for MG patients.

    更新日期:2018-10-23
  • SLAM family receptors in natural killer cells – Mediators of adhesion, activation and inhibition via cis and trans interactions
    Clin. Immunol. (IF 3.557) Pub Date : 2018-10-22
    Maren Claus, Doris Urlaub, Frank Fasbender, Carsten Watzl

    SLAM family receptors are important for the fine-tuning of immune reactions. Their expression is restricted to cells of hematopoietic origin and most SLAM family receptors are their own ligand. Here we review how these receptors are involved in regulating the functions of Natural Killer (NK) cells. We discuss that promoting cellular adhesion may be a main function of SLAM family receptors in NK cells. The homophilic interactions of SLAM family receptors can not only occur in trans between different cells, but also in cis on the surface of the same cell. This cis interaction additionally modulates the function of the receptors and subsequently affects the activities of NK cells. Finally, SLAM-family receptors can also mediate inhibitory signals under certain conditions. These inhibitory signals can contribute to the functional maturation of NK cells during NK cell education. Therefore, SLAM family receptors are critically involved in many aspects of NK cell functionality.

    更新日期:2018-10-23
  • Adolescents and young adults (AYAs) affected by chronic immunological disease: A tool-box for success during the transition to adult care
    Clin. Immunol. (IF 3.557) Pub Date : 2018-10-19
    Aurélien Guffroy, Thierry Martin, Anne-Sophie Korganow

    Adolescence is a time of physical, psychological and social changes between childhood and adulthood. All adolescents and young adults (AYAs) are in transition and experience key underlying processes that will influence their later life. It is a critical period, particularly for AYAs with a chronic medical condition. Diseases can start at any point during adolescence. The transition of care will concern health care providers, as well as more unexpected actors such as social workers, teachers, business managers and the family. In this review, we focus on transition in primary immunodeficiencies (PIDs) and autoimmune diseases (AIDs). We describe the challenges and needs of transition in the field. Questions that AYAs with PID and/or AID must face during transition in their familial, professional and personal life are discussed. We expose a practical, AYA centered approach to help physicians in their daily practice, and we propose a position for the future.

    更新日期:2018-10-22
  • 2B4 (CD244, SLAMF4) and CS1 (CD319, SLAMF7) in systemic lupus erythematosus and cancer
    Clin. Immunol. (IF 3.557) Pub Date : 2018-10-19
    Joseph D. Malaer, Armando M. Marrufo, Porunelloor A. Mathew

    Signaling Lymphocyte Activation Molecule (SLAM) family receptors are expressed on different types of hematopoietic cells and play important role in immune regulation in health and disease. 2B4 (CD244, SLAMF4) and CS1 (CD319, CRACC, SLAMF7) were originally identified as NK cell receptors regulating NK cell cytolytic activity. 2B4 is expressed on all NK cells, a subpopulation of T cells, monocytes and basophils. Unlike other activating and inhibitory receptors, 2B4 (CD244) interaction with its ligand CD48 has been shown to mediate both activating and inhibitory functions. Defective signaling via 2B4 due to mutations in signaling adaptor SAP contributes to X-linked lymphoproliferative Disease (XLP). Expression of 2B4 and CS1 are altered in systemic lupus erythematosus (SLE). CS1 is overexpressed in multiple myeloma (MM) and anti-CS1 mab (Elotuzumab/Empliciti) has been approved by FDA as a breakthrough drug for treatment for MM patients. CAR -T cells or CAR- NK cells containing full length CS1 or the signaling domain of 2B4 with TCR-ζ have shown promising results to treat cancer and autoimmune diseases.

    更新日期:2018-10-22
  • BTK inhibition ameliorates kidney disease in spontaneous lupus nephritis
    Clin. Immunol. (IF 3.557) Pub Date : 2018-10-16
    Samantha A. Chalmers, Elizabeth Glynn, Sayra J. Garcia, Mark Panzenbeck, Josephine Pelletier, Janice Dimock, Elise Seccareccia, Todd Bosanac, Sara Khalil, Christian Harcken, Deborah Webb, Gerald Nabozny, Jay S. Fine, Donald Souza, Elliott Klein, Leal Herlitz, Meera Ramanujam, Chaim Putterman

    Lupus nephritis is a common disease manifestation of SLE, in which immune complex deposition and macrophage activation are important contributors to disease pathogenesis. Bruton's tyrosine kinase (BTK) plays an important role in both B cell and FcgammaR mediated myeloid cell activation. In the current study, we examined the efficacy of BI-BTK-1, a recently described irreversible BTK inhibitor, in the classical NZB × NZW F1 (NZB/W) and MRL/lpr spontaneous mouse models of SLE. NZB/W mice were randomly assigned to a treatment (0.3 mg/kg, 1 mg/kg, 3 mg/kg and 10 mg/kg) or control group and began treatment at 22 weeks of age. The experimental setup was similar in MRL/lpr mice, but with a single treated (10 mg/kg, beginning at 8–9 weeks of age) and control group. A separate experiment was performed in the MRL/lpr strain to assess the ability of BI-BTK-1 to reverse established kidney disease. Early treatment with BI-BTK-1 significantly protected NZB/W and MRL/lpr mice from the development of proteinuria, correlating with significant renal histological protection, decreased anti-DNA titers, and increased survival in both strains. BI-BTK-1 treated mice displayed a significant decrease in nephritis-associated inflammatory mediators (e.g. LCN2 and IL-6) in the kidney, combined with a significant inhibition of immune cell infiltration and accumulation. Importantly, BI-BTK-1 treatment resulted in the reversal of established kidney disease. BTK inhibition significantly reduced total B cell numbers and all B cell subsets (immature, transitional, follicular, marginal zone, and class switched) in the spleen of NZB/W mice. Overall, the significant efficacy of BI-BTK-1 in ameliorating multiple pathological endpoints associated with kidney disease in two distinct murine models of spontaneous lupus nephritis provides a strong rationale for BTK inhibition as a promising treatment approach for lupus nephritis.

    更新日期:2018-10-17
  • The role of surface molecule CD229 in Multiple Myeloma
    Clin. Immunol. (IF 3.557) Pub Date : 2018-10-13
    Michael Olson, Sabari Radhakrishnan, Tim Luetkens, Djordje Atanackovic

    The outcome of Multiple Myeloma (MM) patients has dramatically improved, however, most patients will still succumb to their disease. Additional therapeutic options are urgently needed and novel immunotherapies are enormously promising in the therapeutic armamentarium against MM. The first step in the development of any immunotherapy needs to be the identification of an appropriate target structure. In this review we present the current knowledge on surface molecule CD229, a member of the Signaling Lymphocyte Activation (SLAM) family of immune receptors. We believe that based on its characteristics, including (1) strong and homogenous expression on all myeloma cells, (2) expression on myeloma precursors, (3) absence from most normal tissues, (4) a central function in the biology of MM, CD229 (SLAMF3) represents a promising target for anti-MM immunotherapies. The introduction of novel anti-CD229 approaches into the clinic will hopefully lead to more durable responses, or maybe even cures, in MM.

    更新日期:2018-10-14
  • Serum miRNA-371b-5p and miRNA-5100 act as biomarkers for systemic lupus erythematosus
    Clin. Immunol. (IF 3.557) Pub Date : 2018-10-07
    Li Zeng, Jia-li Wu, Li-min Liu, Ju-qing Jiang, Hai-jing Wu, Ming Zhao, Qian-jin Lu

    MicroRNAs (miRNAs) play important roles in the pathogenesis of systemic lupus erythematosus (SLE). Here, we investigated the serum miRNAs expression profiles in the serum of SLE and healthy controls, and identified the potential serum biomarkers for SLE. We screened and identified the differentially expressed miRNAs such as miR-371b-5p, miR-5100, miR-146a-5p among active SLE, inactive SLE and healthy controls based on the miRNAs expression array. Furthermore, the results of RT-qPCR confirmed that miR-371b-5p and miR-5100 expression was different among active SLE, inactive SLE and healthy controls. Moreover, we performed in a large cohort which we validated that expression of miR-371b-5p and miR-5100 was increased significantly in the serum of SLE compared with healthy controls and rheumatoid arthritis (RA), and was also higher in active SLE than that in inactive SLE. In addition, we found the associations between the expression levels of miR-371b-5p and miR-5100 and these clinical parameters of SLE. These results suggested that miR-371b-5p and miR-5100 may act as serum biomarkers for SLE.

    更新日期:2018-10-08
  • Fra-2 is a novel candidate drug target expressed in the podocytes of lupus nephritis
    Clin. Immunol. (IF 3.557) Pub Date : 2018-10-05
    Changliang Xu, Yunjie Miao, Qingmeng Pi, Shoucao Zhu, Furong Li

    Lupus nephritis (LN) is a common and devastating complication caused by systemic lupus erythematosus. In this study, we evaluated the expression and mechanism of Fos-related antigen 2 (Fra-2) in LN. The results showed that Fra-2 was significantly increased in kidney biopsies of LN patients compared with healthy controls and other kidney disease in glomerular podocytes. The MRL/lpr mouse strain is a murine model of lupus, and it was used to study the mechanisms of Fra-2 in LN. The results showed that Fra-2 was expressed in the glomerular podocytes. We investigated the effects of inflammatory stimuli on Fra-2 protein expression in the glomerular podocytes, and found that interferon gamma was most effective at increasing Fra-2 protein expression. Knockdown of Fra-2 using siRNA enhanced the protein expression of nephrin. Therefore, Fra-2 may be a specific drug target for podocyte injury in LN.

    更新日期:2018-10-06
  • Podocyte foot process width is a prediction marker for complete renal response at 6 and 12 months after induction therapy in lupus nephritis
    Clin. Immunol. (IF 3.557) Pub Date : 2018-10-05
    Kunihiro Ichinose, Mineaki Kitamura, Shuntaro Sato, Keita Fujikawa, Yoshiro Horai, Naoki Matsuoka, Masahiko Tsuboi, Fumiaki Nonaka, Toshimasa Shimizu, Shoichi Fukui, Masataka Umeda, Tomohiro Koga, Shin-ya Kawashiri, Naoki Iwamoto, Takashi Igawa, Mami Tamai, Hideki Nakamura, Tomoki Origuchi, Atsushi Kawakami

    Morphological change that includes diffuse effacement of podocyte foot processes is correlated with proteinuria in patients with lupus nephritis (LN). We collected the data of clinico-pathological parameters and assessed foot process width (FPW) as an index of podocyte effacement in 73 patients with LN who had undergone renal biopsy. The multivariate analysis revealed that female gender (OR: 5.288; 95%CI: 1.197–37.29; p = .0267) and FPW (OR = 0.999, 95%CI = 0.997–0.999, p = .0150) were significantly predictive of a complete renal response (CR) at 6 months, while lymphocyte counts (OR = 1.002; 95%CI = 1.001–1.003, p = .0028) and FPW (OR = 0.998, 95%CI = 0.996–0.999, p = .0027) were significantly predictive of CR at 12 months. The cut-off point determined by the Classification and Regression Trees algorithm showed that FPW <908.3 nm provides the best performance for predicting patients who achieve CR at 12 months. A smaller FPW appears to be a predictive factor for CR at 6 and 12 months after induction therapy.

    更新日期:2018-10-06
  • The relationship between autophagy, increased neutrophil extracellular traps formation and endothelial dysfunction in chronic kidney disease
    Clin. Immunol. (IF 3.557) Pub Date : 2018-10-06
    Jwa-Kyung Kim, Mi Jin Park, Hoi Woul Lee, Hyung Seok Lee, Sun Ryoung Choi, Young Rim Song, Hyung Jik Kim, Hyeong-Cheon Park, Sung Gyun Kim

    In chronic kidney disease (CKD), the number of circulating neutrophils are increased, and this is usually accompanied by an increased basal activation state. However, the possible association between neutrophil extracellular traps (NETs) with vascular complications has not been evaluated. We assessed the relationship between NETs, autophagy and endothelial dysfunction in maintenance hemodialysis (MHD) patients. NET formation, neutrophil elastase (NE) activities, and serum nucleosome levels were measured in MHD (n = 60) and controls (n = 20). Basal NET formation were markedly increased in MHD patient compared to controls. After PMA stimulation, MHD neutrophils showed significantly increased NETs formation response than controls. The degree of NETs was strongly associated with lower flow-mediated dilatation(%) of brachial artery even after adjustment for cardiovascular risk factors and uremic toxins. Moreover, MHD neutrophils showed increased basal autophagy activity. Interestingly, the levels of NETs were markedly augmented after autophagy inhibition, suggesting a protective role of autophagy in excessive NET formation.

    更新日期:2018-10-06
  • The heterogeneity of autoimmune polyendocrine syndrome type 1: Clinical features, new mutations and cytokine autoantibodies in a Brazilian cohort from tertiary care centers
    Clin. Immunol. (IF 3.557) Pub Date : 2018-10-01
    Fernanda Guimarães Weiler, Pärt Peterson, Beatriz Tavares Costa-Carvalho, Mayra de Barros Dorna, Joya Emilie de Menezes Correia-Deur, Soraya Lopes Sader, Daniela Espíndola-Antunes, Gil Guerra-Junior, Magnus Régios Dias-da-Silva, Marise Lazaretti-Castro

    Autoimmune polyendocrine syndrome type 1 (APS1) is characterized by multiorgan autoimmunity. We aim at characterizing a multi-center Brazilian cohort of APS1 patients by clinical evaluation, searching mutation in the AIRE gene, measuring serum autoantibodies, and investigating correlations between findings. We recruited patients based on the clinical criteria and tested them for AIRE mutations, antibodies against interferon type I and interleukins 17A, 17F and 22. We identified 12 unrelated families (13 patients) with typical signs of APS1 in the proband, and the screening of relatives recognized an asymptomatic child. Candidiasis was present in all cases, and 19 other manifestations were observed. All patients carried one of 10 different mutations in AIRE, being 3 new ones, and were positive for anti-interferon type I serum antibody. Anti-interleukin-17A levels inversely correlated with the number of manifestations in each patient. This negative correlation may suggest a protective effect of anti-interleukin-17A with a potential therapeutic application.

    更新日期:2018-10-02
  • Flow cytometric assessment of leukocyte kinetics for the monitoring of tissue damage
    Clin. Immunol. (IF 3.557) Pub Date : 2018-10-02
    Wouter B.L. van den Bossche, Kyrill Rykov, Cristina Teodosio, Bas L.E.F. ten Have, Bas A.S. Knobben, Maurits S. Sietsma, Karin Josiassen, Sandra de Bruin - Versteeg, Alberto Orfao, Jacques J.M. van Dongen, Jos J.A.M. van Raay

    Leukocyte populations quickly respond to tissue damage, but most leukocyte kinetic studies are not based on multiparameter flow cytometry. We systematically investigated several blood leukocyte populations after controlled tissue damage. 48 patients were assigned to either an anterior or posterolateral total hip arthroplasty. Peripheral blood was collected pre-operatively and at 2 h, 24 h, 48 h, 2 and 6 weeks postoperatively and assessed by flow cytometry for absolute counts of multiple leukocyte populations using standardized EuroFlow protocols. Absolute counts of leukocyte subsets differed significantly between consecutive time points. Neutrophils increased instantly after surgery, while most leukocyte subsets initially decreased, followed by increasing cell counts until 48 h. At two weeks all leukocyte counts were restored to pre-operative counts. Immune cell kinetics upon acute tissue damage exhibit reproducible patterns, which differ between the leukocyte subsets and with “opposite kinetics” among monocyte subsets. Flow cytometric leukocyte monitoring can be used to minimally invasively monitor tissue damage.

    更新日期:2018-10-02
  • Exome sequencing confirms diagnosis of kabuki syndrome in an-adult with hodgkin lymphoma and unusually severe multisystem phenotype
    Clin. Immunol. (IF 3.557) Pub Date : 2018-09-30
    Charu Kaiwar, Teresa M. Kruisselbrink, Yogish C. Kudva, Eric W. Klee, Pavel Pichurin

    We report a 34-year-old male patient with a novel variant in KMT2D gene, which finally ended a quest for a diagnosis that was clinically suspected in the past, prior the molecular basis of Kabuki Syndrome (KS) was known. The patient showcases the multisystemic features, with involvement of all previously associated with KS body systems, presence of immune deficiency as well as autoimmune disorders, requiring three pancreatic transplants. We also report, for the first time to our knowledge, the presence of epidural lipomatosis and Hodgkin Lymphoma in a patient with KS.

    更新日期:2018-10-01
  • Regulation of systemic tissue injury by coagulation inhibitors in B6.MRL/lpr autoimmune mice
    Clin. Immunol. (IF 3.557) Pub Date : 2018-09-25
    C. Moratz, R. Robbins, J. Eickhoff, J. Edison, H. Lui, S. Peng

    Impaired fibrinolysis and complement activation in Systemic Lupus Erythematosus contributes to disease amplification including increased risk of thrombosis and tissue Ischemia/Reperfusion (IR) injury. Previous work has demonstrated complement is a key regulator of tissue injury. In these studies inhibitors had varying efficacies in attenuating injury at primary versus systemic sites, such as lung. In this study the role of coagulation factors in tissue injury and complement function was evaluated. Tissue Factor Pathway Inhibitor (TFPI), an extrinsic pathway inhibitor, and Anti-Thrombin III, the downstream common pathway inhibitor, were utilized in this study. TFPI was more effective in attenuated primary intestinal tissue injury. However both attenuated systemic lung injury. However, ATIII treatment resulting in enhanced degradation of C3 split products in lung tissue compared to TFPI. This work delineates the influence of specific early and late coagulation pathway components during initial tissue injury versus later distal systemic tissue injury mechanism.

    更新日期:2018-09-26
  • Tolerogenic dendritic cells induced the enrichment of CD4+Foxp3+ regulatory T cells via TGF-β in mesenteric lymph nodes of murine LPS-induced tolerance model
    Clin. Immunol. (IF 3.557) Pub Date : 2018-09-21
    Li Jia, Jia Lu, Ya Zhou, Yijing Tao, Hualin Xu, Wen Zheng, Juanjuan Zhao, Guiyou Liang, Lin Xu

    Endotoxin tolerance is an important state for the prevention of lethal infection and inflammatory response, which is closely associated with the participation of innate immune cells. Moreover, mesenteric lymph nodes (MLNs)-resident immune cells, such as CD4+Foxp3+ regulatory T (Treg) cells and dendritic cells, play important roles in the maintenance of peripheral immune tolerance. However, the potential roles of these cells in MLNs in the development of endotoxin tolerance remain largely unknown. Recent research work showed that CD4+Foxp3+ Treg cells contributed to the development of endotoxin tolerance. Here, we further analyzed the possible change on CD4+Foxp3+Tregs population in MLNs in murine LPS-induced endotoxin tolerance model. Our data showed that the proportion and absolute number of CD4+Foxp3+Tregs, expressing altered levels of CTLA4 and GITR, significantly increased in MLNs of murine LPS-induced tolerance model. Moreover, the expression level of TGF-β in MLNs also increased obviously. Furthermore, TGF-β blockade could obviously reduce the proportion and absolute number of CD4+Foxp3+Tregs in MLNs and subsequently impair the protection effect against LPS rechallenge. Of note, we found that tolerogenic dendritic cell (Tol-DC), expressing lower levels of MHC-II and CD86 molecules, dominantly secreted TGF-β in MLNs in murine LPS-induced tolerance model. In all, our data provided an unknown phenomenon that the total cell number of CD4+Foxp3+Tregs significantly increased in MLNs in endotoxin tolerance, which was related to MLN-resident TGF-β secreting CD11c+DCs, providing a new fundamental basis for the understanding on the potential roles of MLN-resident immune cells in the development of endotoxin tolerance.

    更新日期:2018-09-22
  • Norovirus-specific mucosal antibodies correlate to systemic antibodies and block norovirus virus-like particles binding to histo-blood group antigens
    Clin. Immunol. (IF 3.557) Pub Date : 2018-09-19
    Kirsi Tamminen, Maria Malm, Timo Vesikari, Vesna Blazevic

    The best acknowledged correlate of protection from norovirus (NoV) infection is the ability of serum antibodies to block binding of NoV virus-like particles (VLPs) to histo-blood group antigens (HBGAs). We investigated mucosal NoV-specific antibody levels in adult volunteers and used saliva from a single donor to determine whether purified saliva antibodies confer blocking. NoV-specific IgG and IgA levels in saliva and plasma samples were measured against four NoV genotype VLPs. NoV-specific IgG and IgA titers in saliva and plasma samples correlated significantly. Antibodies were detected against all VLPs with the highest level of antibodies directed against ancestral GII.4 99 genotype. Affinity chromatography purified salivary IgA and IgG blocked binding of GII.4 99 VLPs to HBGAs. Saliva sampling is a non-invasive alternative to blood drawing and an excellent biological fluid to study NoV-specific immune responses. Mucosal anti-NoV antibodies block binding of NoV VLPs to HBGAs, and may therefore be protective.

    更新日期:2018-09-20
  • CVID enteropathy is characterized by exceeding low mucosal iga levels and interferon-driven inflammation possibly related to the presence of a pathobiont
    Clin. Immunol. (IF 3.557) Pub Date : 2018-09-19
    Natalia Shulzhenko, Xiaoxi Dong, Dariia Vyshenska, Renee L. Greer, Manoj Gurung, Stephany Vasquez-Perez, Ekaterina Peremyslova, Stanislav Sosnovtsev, Martha Quezado, Michael Yao, Kim Montgomery-Recht, Warren Strober, Ivan J. Fuss, Andrey Morgun

    Common variable immunodeficiency (CVID), the most common symptomatic primary antibody deficiency, is accompanied in some patients by a duodenal inflammation and malabsorption syndrome known as CVID enteropathy (E-CVID). The goal of this study was to investigate the immunological abnormalities in CVID patients that lead to enteropathy as well as the contribution of intestinal microbiota to this process. We found that, in contrast to noE-CVID patients (without enteropathy), E-CVID patients have exceedingly low levels of IgA in duodenal tissues. In addition, using transkingdom network analysis of the duodenal microbiome, we identified Acinetobacter baumannii as a candidate pathobiont in E-CVID. Finally, we found that E-CVID patients exhibit a pronounced activation of immune genes and down-regulation of epithelial lipid metabolism genes. We conclude that in the virtual absence of mucosal IgA, pathobionts such as A. baumannii, may induce inflammation that re-directs intestinal molecular pathways from lipid metabolism to immune processes responsible for enteropathy.

    更新日期:2018-09-20
  • NLRP3 inflammasome regulates Th17 differentiation in rheumatoid arthritis
    Clin. Immunol. (IF 3.557) Pub Date : 2018-09-17
    Chunmei Zhao, Yibin Gu, Xiaoyun Zeng, Jing Wang

    Rheumatoid arthritis (RA) is one of the most common autoimmune diseases. Th17 has been shown to play am important role in the pathogenesis of RA. Accumulating data suggest the involvement of NLRP3 inflammasome in Th17 differentiation in autoimmune diseases. In the current study, we found that NLRP3 inflammasome is activated in CD4 T cells from RA patients. The activation of NLRP3 inflammasome was correlated with disease activities and IL-17A concentration in RA sera. Knockdown of NLRP3 suppressed Th17 differentiation. In addition, caspase-1 or IL-1 receptor inhibitor inhibits Th17 differentiation significantly. Further, ROS production is increased in CD4 T cells from RA patients. The inhibition of ROS production decreased NLRP3 inflammasome activation and IL-1β production in CD4 T cells, leading to the suppression of Th17 differentiation. These findings suggest a pathogenic role of NLRP3 inflammasome in RA by promoting Th17 cell differentiation. NLRP3 inflammasome could be a potential therapeutic target for the treatment of RA.

    更新日期:2018-09-18
  • Increase of follicular helper T cells skewed toward a Th1 profile in CVID patients with non-infectious clinical complications
    Clin. Immunol. (IF 3.557) Pub Date : 2018-09-13
    Delphine Turpin, Adeline Furudoi, Marie Parrens, Patrick Blanco, Jean-François Viallard, Dorothée Duluc

    Common variable immunodeficiency (CVID) is characterized by low levels of circulating immunoglobulins and defects in B cell maturation leading to an increased susceptibility to infections. Some patients develop complications such as autoimmune diseases, enteropathy, and lymphoproliferation, resulting in higher morbidity and mortality. Follicular helper T (Tfh) cells are specialized in helping B cell differentiation into Ig-producing cells. Three subsets have been described, namely non B-cell helper Tfh1 and the two B-helper cell subsets Tfh2 and Tfh17. We determined that circulating Tfh cells were elevated in CVID patients and skewed toward a Tfh1 profile. Interestingly, elevated levels of Tfh1 cells were significant only in patients harboring non-infectious complications regardless of the type of complication and inversely correlated with switched memory B cells. Moreover, CXCR3+ cells are increased in splenic CVID germinal centers. Our observations suggest that the altered balance in Tfh subsets in CVID is linked to a more severe disease.

    更新日期:2018-09-14
  • Th17 and Treg lymphocytes in obesity and Type 2 diabetic patients
    Clin. Immunol. (IF 3.557) Pub Date : 2018-09-13
    Mei Wang, Fuqiong Chen, Jingli Wang, Zhixuan Zeng, Qin Yang, Shiying Shao

    Assumption that the pathogenesis of obesity-associated type 2 diabetes (T2DM) encompasses inflammation and autoimmune aspects is increasingly recognized. In the state of obesity and T2DM, the imbalance of T helper 17 (Th17) cells and regulatory T (Treg) cells are observed. These alterations reflect a loss of T cell homeostasis, which may contribute to tissue and systemic inflammation and immunity in T2DM. In this review we will discuss the accumulating data supporting the concept that Th17/Treg mediated immune responses are present in obesity-related T2DM pathogenesis, and provide evidences that restoration of Th17/Treg imbalance may be a possible therapeutic avenue for the prevention and treatment of T2DM and its complications.

    更新日期:2018-09-13
  • Immunogenicity to cerliponase alfa intracerebroventricular enzyme replacement therapy for CLN2 disease: Results from a Phase 1/2 study
    Clin. Immunol. (IF 3.557) Pub Date : 2018-09-08
    Anu Cherukuri, Heather Cahan, Greg de Hart, Andrea Van Tuyl, Peter Slasor, Laurie Bray, Josh Henshaw, Temitayo Ajayi, Dave Jacoby, Charles A. O'Neill, Becky Schweighardt

    Treatment with intracerebroventricular (ICV)-delivered cerliponase alfa enzyme replacement therapy (ERT) in a Phase 1/2 study of 24 subjects with CLN2 disease resulted in a meaningful preservation of motor and language (ML) function and was well tolerated. Treatment was associated with anti-drug antibody (ADA) production in the cerebrospinal fluid (CSF) of 6/24 (25%) and in the serum of 19/24 (79%) of clinical trial subjects, respectively, over a mean exposure of 96.4 weeks (range 0.1–129 weeks). Neutralizing antibodies (NAb) were not detected in the CSF of any of the subjects. No events of anaphylaxis were reported. Neither the presence of serum ADA nor drug-specific immunoglobulin E was associated with the incidence or severity of hypersensitivity adverse events. Serum and CSF ADA titers did not correlate with change in ML score. Therefore, the development of an ADA response to cerliponase alfa is not predictive of an adverse safety profile or poor treatment outcome.

    更新日期:2018-09-09
  • Pathophysiology and inhibition of IL-23 signaling in psoriatic arthritis: A molecular insight
    Clin. Immunol. (IF 3.557) Pub Date : 2018-09-06
    Cuong Thach Nguyen, Yehudi Bloch, Katarzyna Składanowska, Savvas N. Savvides, Iannis E. Adamopoulos

    Psoriatic arthritis (PsA) is a chronic inflammatory arthritis of unknown etiology, and currently the cellular and molecular interactions that dictate its pathogenesis remain elusive. A role of the interleukin-23 (IL-23)/IL-23R (IL-23 receptor) interaction in the development of psoriasis and PsA is well established. As IL-23 regulates the differentiation and activation of innate and adaptive immunity, it pertains to a very complex pathophysiology involving a plethora of effectors and transducers. In this review, we will discuss recent advances on the cellular and molecular pathophysiological mechanisms that regulate the initiation and progression of PsA as well as new therapeutic approaches for IL-23/IL-23R targeted therapeutics.

    更新日期:2018-09-07
  • Importance of TLR9-IL23-IL17 axis in inflammatory bowel disease development: Gene expression profiling study
    Clin. Immunol. (IF 3.557) Pub Date : 2018-09-05
    Sanja Dragasevic, Biljana Stankovic, Aleksandra Sokic-Milutinovic, Tomica Milosavljevic, Tamara Milovanovic, Snezana Lukic, Sanja Srzentic Drazilov, Kristel Klaassen, Nikola Kotur, Sonja Pavlovic, Dragan Popovic

    Background and aims Mucosal gene expression have not been fully enlightened in inflammatory bowel disease (IBD). Aim of this study was to define IL23A, IL17A, IL17F and TLR9 expression in different IBD phenotypes. Methods Evaluation of mRNA levels was performed in paired non-inflamed and inflamed mucosal biopsies of newly diagnosed 50 Crohn's disease (CD) and 54 ulcerative colitis (UC) patients by quantitative real-time PCR analysis. Results IL17A and IL17F expression levels were significantly increased in inflamed IBD mucosa. Inflamed CD ileal and UC mucosa showed increased IL23A, while only inflamed CD ileal samples showed increased TLR9 mRNA level. Correlation between analysed mRNAs levels and endoscopic and clinical disease activity were found in UC, but only with clinical activity in CD. Conclusion Both CD and UC presented expression of Th17-associated genes. Nevertheless, expression profiles between different disease forms varies which should be taken into account for future research and therapeutics strategies.

    更新日期:2018-09-05
  • Cytokine targets in lupus nephritis: Current and future prospects
    Clin. Immunol. (IF 3.557) Pub Date : 2018-09-02
    Christina Adamichou, Spyros Georgakis, George Bertsias

    Despite advancements in the care of lupus nephritis, a considerable proportion of patients may respond poorly or flare while on conventional immunosuppressive agents. Studies in murine and human lupus have illustrated a pathogenic role for several cytokines by enhancing T- and B-cell activation, autoantibodies production and affecting the function of kidney resident cells, therefore supporting their potential therapeutic targeting. To this end, there is limited post-hoc randomized evidence to suggest beneficial effect of belimumab, administered on top of standard-of-care, during maintenance therapy in lupus nephritis. Type I interferon receptor blockade has yielded promising results in preliminary SLE trials yet data on renal activity are unavailable. Conversely, targeting interleukin-6 and interferon-γ both failed to demonstrate a significant renal effect. For several other targets, preclinical data are encouraging but will require confirmation. We envision that high-throughput technologies will enable accurate patient stratification, thus offering the opportunity for personalized implementation of cytokine-targeting therapies.

    更新日期:2018-09-03
  • Indoleamine-2,3-dioxygenase in murine and human systemic lupus erythematosus: Down-regulation by the tolerogeneic peptide hCDR1
    Clin. Immunol. (IF 3.557) Pub Date : 2018-08-28
    Zev Sthoeger, Amir Sharabi, Heidy Zinger, Ilan Asher, Edna Mozes

    וֹndoleamine-2,3-dioxygenase (IDO) plays a role in immune regulation. Increased IDO activity was reported in systemic lupus erythematosus (SLE). We investigated the effects of the tolerogenic peptide hCDR1, shown to ameliorate lupus manifestations, on IDO gene expression. mRNA was prepared from splenocytes of hCDR1- treated SLE-afflicted (NZBxNZW)F1 mice, from blood samples of lupus patients, collected before and after their in vivo treatment with hCDR1 and from peripheral blood mononuclear cells (PBMC) of patients incubated with hCDR1. IDO gene expression was determined by real-time RT-PCR. hCDR1 significantly down-regulated IDO expression in SLE-affected mice and in lupus patients (treated in vivo and in vitro). No effects were observed in healthy donors or following treatment with a control peptide. Diminished IDO gene expression was associated with hCDR1 beneficial effects. Our results suggest that the hCDR1-induced FOXP3 expressing regulatory T cells in lupus are not driven by IDO but rather by other hCDR1 regulated pathways.

    更新日期:2018-08-29
  • Oxidative stress and dietary micronutrient deficiencies contribute to overexpression of epigenetically regulated genes by lupus T cells
    Clin. Immunol. (IF 3.557) Pub Date : 2018-04-11
    Donna Ray, Faith M. Strickland, Bruce C. Richardson

    Patients with active lupus have altered T cells characterized by low DNA methyltransferase levels. We hypothesized that low DNA methyltransferase levels synergize with low methionine levels to cause greater overexpression of genes normally suppressed by DNA methylation. CD4+ T cells from lupus patients and controls were stimulated with PHA then cultured in custom media with normal or low methionine levels. Oxidative stress was induced by treating the normal CD4+ T cells with peroxynitrite prior to culture. Methylation sensitive gene expression was measured by flow cytometry. Results showed low methionine levels caused greater overexpression of methylation sensitive genes in peroxynitrite treated T cells relative to untreated T cells, and in T cells from lupus patients relative to T cells from healthy controls. In conclusion, low dietary transmethylation micronutrient levels and low DNA methyltransferase levels caused either by oxidative stress or lupus, have additive effects on methylation sensitive T cell gene expression.

    更新日期:2018-07-14
  • Maternal T-cell engraftment impedes with diagnosis of a SCID-ADA patient
    Clin. Immunol. (IF 3.557) Pub Date : 2018-05-07
    Arnalda Lanfranchi, Vassilios Lougaris, Lucia Dora Notarangelo, Elena Soncini, Marta Comini, Alessandra Beghin, Federica Bolda, Alessandro Montanelli, Luisa Imberti, Fulvio Porta

    We describe the case of a child affected by severe combined immunodeficiency (SCID) with adenosine deaminase (ADA) deficiency showing a maternal T-cell engraftment, a finding that has never been reported before. The presence of engrafted maternal T cells was misleading. Although ADA enzymatic levels were suggestive of ADA-SCID, the child did not present the classical signs of ADA deficiency; therefore, the initial diagnosis was of a conventional SCID. However, ADA toxic metabolites and molecular characterization confirmed this diagnosis. Polyethylene glycol-modified bovine (PEG) ADA therapy progressively decreased the number of maternal engrafted T cells. The child was grafted with full bone marrow from a matched unrelated donor, after a reduced conditioning regimen, and the result was the complete immunological reconstitution.

    更新日期:2018-05-08
  • A mechanism of interleukin-25 production from airway epithelial cells induced by Japanese cedar pollen
    Clin. Immunol. (IF 3.557) Pub Date : 2018-05-07
    Hideaki Kouzaki, Hirotaka Kikuoka, Koji Matsumoto, Tomohisa Kato, Ichiro Tojima, Shino Shimizu, Takeshi Shimizu

    IL-25 likely has vital roles in initiating and activating type-2 immune responses in AR. We hypothesized that the molecules produced IL-25 by allergen-producing organisms such as JC is involved in the pathogenesis of AR. Participants included 13 patients with Japanese cedar pollinosis and 10 HCs. We measured the IL-25 protein concentration in nasal secretions and in culture supernatants of PNECs. NHBE cells were stimulated with pharmacological and immunological agents and JC. The IL-25 concentration in nasal secretions was significantly higher in patients with Japanese cedar pollinosis than in HCs. JC stimulated IL-25 production from PNECs. TNF-α, IL-4, and IL-13 significantly enhanced JC-induced IL-25 production; their activation by serine proteases was sufficient to enhance IL-25 production. Furthermore, the NADPH oxidase activity, including JC enhanced IL-25 production. A better understanding of JC-induced IL-25 production by epithelial cells may allow the development of novel therapeutic and preventive strategies for Japanese cedar pollinosis.

    更新日期:2018-05-08
  • The tolerogenic peptide hCDR1 immunomodulates cytokine and regulatory molecule gene expression in blood mononuclear cells of primary Sjogren's syndrome patients
    Clin. Immunol. (IF 3.557) Pub Date : 2018-05-04
    Zev Sthoeger, Amir Sharabi, Ilan Asher, Heidy Zinger, Rafael Segal, Gene Shearer, Ori Elkayam, Edna Mozes

    Primary Sjogren‘s syndrome (pSS) is an autoimmune disease characterized by lymphocytic infiltration of exocrine glands. We investigated whether the tolerogenic peptide, hCDR1, that ameliorates lupus manifestations would have beneficial effects on pSS as well. The in vitro effects of hCDR1 on gene expression of pro-inflammatory cytokines and regulatory molecules were tested in peripheral blood mononuclear cells (PBMC) of 16 pSS patients. hCDR1, but not a control peptide, significantly reduced gene expression of IL-1β, TNF-α, MX-1 and BlyS and up-regulated immunosuppressive (TGF-β, FOXP3) molecules in PBMC of pSS patients. hCDR1 did not affect gene expression in patients with rheumatoid arthritis and anti-phospholipid syndrome. Further, hCDR1 up-regulated the expression of Indoleamine 2,3-dioxygenase (IDO) via elevation of TGF-β. IDO inhibition led to a significant decrease in the expression of FOXP3 which is crucial for the induction of T regulatory cells. Thus, hCDR1 is potential candidate for the specific treatment of pSS patients.

    更新日期:2018-05-04
  • CD14+ monocytes contribute to inflammation in chronic nonbacterial osteomyelitis (CNO) through increased NLRP3 inflammasome expression
    Clin. Immunol. (IF 3.557) Pub Date : 2018-04-30
    D. Brandt, E. Sohr, J. Pablik, A. Schnabel, F. Kapplusch, K. Mäbert, J.H. Girschick, H. Morbach, F. Thielemann, S.R. Hofmann, C.M. Hedrich

    The pathophysiology of chronic nonbacterial osteomyelitis (CNO) remains incompletely understood. Increased NLRP3 inflammasome activation and IL-1β release in monocytes from CNO patients was suggested to contribute to bone inflammation. Here, we dissect immune cell infiltrates and demonstrate the involvement of monocytes across disease stages. Differences in cell density and immune cell composition may help to discriminate between BOM and CNO. However, differences are subtle and infiltrates vary in CNO. In contrast to other cells involved, monocytes are a stable element during all stages of CNO, which makes them a promising candidate in the search for “drivers” of inflammation. Furthermore, we link increased expression of inflammasome components NLRP3 and ASC in monocytes with site-specific DNA hypomethylation around the corresponding genes NLRP3 and PYCARD. Our observations deliver further evidence for the involvement of pro-inflammatory monocytes in the pathophysiology of CNO. Cellular and molecular alterations may serve as disease biomarkers and/or therapeutic targets.

    更新日期:2018-05-01
  • Alpha-lactose reverses liver injury via blockade of Tim-3-mediated CD8 apoptosis in sepsis
    Clin. Immunol. (IF 3.557) Pub Date : 2018-04-22
    Zhengping Wei, Pingfei Li, Yao Yao, Hai Deng, Shengwu Yi, Cong Zhang, Han Wu, Xiuxiu Xie, Minghui Xia, Ran He, Xiang-Ping Yang, Zhao-Hui Tang

    In sepsis, the liver plays a crucial role in regulating immune responses and is also a target organ for immune-related injury. Despite the critical function of CD8+ T cells against opportunistic viral infections, the CD8 immune response in the liver during sepsis remains elusive. Here we found that Tim-3 is highly up-regulated in liver CD8+ T cells in a mouse cecal ligation and puncture model and in peripheral blood CD8+ T cells of human patients with sepsis. The expression of Tim-3 in liver CD8+ T cells displayed a bi-phasic pattern and deletion of Tim-3 led to reduction of CD8+ T cell apoptosis. Administration of α-lactose, a molecule with a similar structure to galactin-9, reduced Tim-3 expression and liver injury in sepsis. Our results demonstrate that targeting Tim-3 to boost CD8+ T cell immune response may offer an improved outcome in patients with sepsis.

    更新日期:2018-04-25
  • Immune senescence, epigenetics and autoimmunity
    Clin. Immunol. (IF 3.557) Pub Date : 2018-04-11
    Donna Ray, Raymond Yung

    Aging of the immune system in humans and animals is characterized by a decline in both adaptive and innate immune responses. Paradoxically, aging is also associated with a state of chronic inflammation (“inflammaging”) and an increased likelihood of developing autoimmune diseases. Epigenetic changes in non-dividing and dividing cells, including immune cells, due to environmental factors contribute to the inflammation and autoimmunity that characterize both the state and diseases of aging. Here, we review the epigenetic mechanisms involved in the development of immune senescence and autoimmunity in old age.

    更新日期:2018-04-11
  • The interaction between environmental triggers and epigenetics in autoimmunity
    Clin. Immunol. (IF 3.557) Pub Date : 2018-04-09
    Bruce Richardson

    Systemic lupus erythematosus flares when genetically predisposed people encounter environmental agents that cause oxidative stress, such as infections and sunlight. How these modify the immune system to initiate flares is unclear. Drug induced lupus models demonstrate that CD4+ T cells epigenetically altered with DNA methylation inhibitors cause lupus in animal models, and similar T cells are found in patients with active lupus. How infections and sun exposure inhibit T cell DNA methylation is unclear. DNA methylation patterns are replicated each time a cell divides in a process that requires DNA methyltransferase one (Dnmt1), which is upregulated as cells enter mitosis, as well as the methyl donor S-adenosylmethionine, created from dietary sources. Reactive oxygen species that inhibit Dnmt1 upregulation, and a diet poor in methyl donors, combine to cause lupus in animal models. Similar changes are found in patients with active lupus, indicating a mechanism contributing to lupus flares.

    更新日期:2018-04-09
  • Elevated expression of TSLP and IL-33 in Behçet's disease skin lesions: IL-37 alleviate inflammatory effect of TSLP
    Clin. Immunol. (IF 3.557) Pub Date : 2018-04-06
    Olfa Kacem, Wajih Kaabachi, Imen Ben Dhifallah, Agnes Hamzaoui, Kamel Hamzaoui

    The release of TSLP and IL-33 affect the skin integrity, which unsettled transcription factor regulators. We investigate TSLP and IL-33 in Behçet disease (BD) and we prove the effect of the anti-inflammatory cytokine IL-37 in BD skin lesions on TSLP production. TSLP, IL-33 and GATA-3/T-bet, were measured using PCR in BD skin lesions. We tested the suppressive effect of IL-37 on skin samples stimulated with a cytokine mixture inducing TSLP expression. TSLP and IL-33 were increased in BD patients particularly in patients having skin manifestations and correlate with indexed skin lesions. TSLP expression in BD with skin lesions correlates significantly with the transcription factors GATA3/Tbet ratio. The anti-inflammatory mediator IL-37 acted as a suppressor of TSLP-skin synthesis. The microenvironment in cutaneous lesions of BD patients' skin lesions is dominated by the expression of IL-33 and TSLP along an inflammatory Th2-type current. IL-37 acts as a booster to restore homeostasis.

    更新日期:2018-04-06
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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