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  • An anti-NMDA receptor encephalitis mimicking an HIV encephalitis
    Clin. Immunol. (IF 3.99) Pub Date : 2018-05-14
    Fatiha Haneche, Sophie Demeret, Dimitri Psimaras, Christine Katlama, Valérie Pourcher

    The incidence of HIV associated neurocognitive disorders (HAND) were reduced with the use of antiretroviral therapy. In case of neuropsychiatric symptoms, after elimination of all infections, auto-immune encephalitis could be evocated as a differential diagnosis. We describe a case of anti-N-Methyl-d-Aspartate receptor encephalitis in an HIV-1 infected woman.

    更新日期:2018-05-14
  • Maternal T-cell engraftment impedes with diagnosis of a SCID-ADA patient
    Clin. Immunol. (IF 3.99) 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 3.99) 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 3.99) 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 3.99) 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 3.99) 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
  • Oxidative stress and dietary micronutrient deficiencies contribute to overexpression of epigenetically regulated genes by lupus T cells ☆
    Clin. Immunol. (IF 3.99) 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:2018-04-12
  • Immune senescence, epigenetics and autoimmunity
    Clin. Immunol. (IF 3.99) 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 3.99) 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 3.99) 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
  • Comparison of efficacy of TNF inhibitors and abatacept in patients with rheumatoid arthritis; Adjusted with propensity score matching
    Clin. Immunol. (IF 3.99) Pub Date : 2018-03-31
    Satoshi Kubo, Shingo Nakayamada, Kazuhisa Nakano, Norifumi Sawamukai, Shintaro Hirata, Kentaro Hanami, Kazuyoshi Saito, Yoshiya Tanaka

    The aim of this study was to compare the clinical outcome of patients with rheumatoid arthritis seen in routine clinical practice treated with either TNF inhibitors or abatacept. To overcome potential bias, both propensity score matching and Inverse Probability of Treatment Weighting were used for patient selection. The propensity score matching procedure selected 315 matched pairs of patients who were treated with TNF inhibitors or abatacept. At week 52, SDAI in TNF inhibitors was lower than abatacept. In contrast, analysis of biologics-naive patients using the propensity-score matching (n = 150; in each group) showed comparable clinical efficacy. Consistent results were obtained by the use of Inverse Probability of Treatment Weighting (581 patients treated with TNF inhibitors and 353 patients treated with abatacept). The predictors of response to each treatment were different; abatacept appeared to benefit patients with high baseline RF titers while TNF inhibitors appeared to benefit patients with low baseline HAQ-DI.

    更新日期:2018-03-31
  • More intensive CMV-infection in chronic heart failure patients contributes to higher T-lymphocyte differentiation degree
    Clin. Immunol. (IF 3.99) Pub Date : 2018-03-30
    Marco Antonio Moro-García, Fernando López-Iglesias, Raquel Marcos-Fernández, Eva Bueno-García, Beatriz Díaz-Molina, José Luis Lambert, Francisco Manuel Suárez-García, Cesar Morís de la Tassa, Rebeca Alonso-Arias

    Immunosenescence in chronic heart failure (CHF) is characterized by a high frequency of differentiated T-lymphocytes, contributing to an inflammatory status and a deficient ability to generate immunocompetent responses. CMV is the best known inducer of T-lymphocyte differentiation, and is associated with the phenomenon of immunosenescence. In this study, we included 58 elderly chronic heart failure patients (ECHF), 60 healthy elderly controls (HEC), 40 young chronic heart failure patients (YCHF) and 40 healthy young controls (HYC). High differentiation of CD8+ T-lymphocytes was found in CMV-seropositive patients; however, the differentiation of CD4+ T-lymphocytes was increased in CMV-seropositive but also in CHF patients. Anti-CMV antibody titers showed positive correlation with more differentiated CD4+ and CD8+ subsets and inverse correlation with CD4/CD8 ratio. Immunosenescence found in CHF patients is mainly due to the dynamics of CMV-infection, since the differentiation of T-lymphocyte subsets is related not only to CMV-infection, but also to anti-CMV antibody titers.

    更新日期:2018-03-31
  • Characterization of Vibrio cholerae neuraminidase as an immunomodulator for novel formulation of oral allergy immunotherapy
    Clin. Immunol. (IF 3.99) Pub Date : 2018-03-30
    Susanne C. Diesner, Cornelia Bergmayr, Xue-Yan Wang, Denise Heiden, Sarah Exenberger, Franziska Roth-Walter, Philipp Starkl, Davide Ret, Isabella Pali-Schöll, Franz Gabor, Eva Untersmayr
    更新日期:2018-03-31
  • Epigenome-wide association studies for systemic autoimmune diseases: The road behind and the road ahead
    Clin. Immunol. (IF 3.99) Pub Date : 2018-03-29
    Elena Carnero-Montoro, Marta E. Alarcón-Riquelme

    Epigenetics is known to be an important mechanism in the pathogenesis of autoimmune diseases. Epigenetic variations can act as integrators of environmental and genetic exposures and propagate activated states in immune cells. Studying epigenetic alterations by means of genome-wide approaches promises to unravel novel molecular mechanisms related to disease etiology, disease progression, clinical manifestations and treatment responses. This paper reviews what we have learned in the last five years from epigenome-wide studies for three systemic autoimmune diseases, namely systemic lupus erythematosus, primary Sjögren's syndrome, and rheumatoid arthritis. We examine the degree of epigenetic sharing between different diseases and the possible mediating role of epigenetic association in genetic and environmental risks. Finally, we also shed light into the use of epigenetic markers towards a better precision medicine regarding disease prediction, prevention and personalized treatment in systemic autoimmunity.

    更新日期:2018-03-30
  • Patients with core antibody positive and surface antigen negative Hepatitis B (anti-HBc+, HBsAg−) on anti-TNF therapy have a low rate of reactivation
    Clin. Immunol. (IF 3.99) Pub Date : 2018-03-28
    William T. Clarke, Shreya S. Amin, Konstantinos Papamichael, Joseph D. Feuerstein, Adam S. Cheifetz

    Anti-TNF agents are widely used to treat immune-mediated disorders. Reactivation of Hepatitis B virus (HBV) is associated with immunosuppressive agents and biologics such as anti-TNF. There are limited data and differing guidelines for patients with negative hepatitis B surface antigen (HBsAg−) but positive antibody to hepatitis B core antigen (anti-HBc+) on anti-TNF with regards to outcomes and need for anti-viral prophylaxis. We examined the prevalence of HBV reactivation in a single-center retrospective cohort study of 120 HBsAg−, anti-HBc+ patients on anti-TNF, totaling 346.6 patient years. One patient (0.8%) who had a detectable VL (<20 IU) prior to starting anti-TNF had reactivation of HBV with sero-conversion to positive HBsAg. Three patients (2.5%) had undetectable HBV VL prior to anti-TNF and developed detectable VL while on anti-TNF. In conclusion, there was a low rate of HBV reactivation or development of detectable HBV DNA in HBsAg−, anti-HBc+ patients on anti-TNF.

    更新日期:2018-03-28
  • Characterization of a large UNC13D gene duplication in a patient with familial hemophagocytic lymphohistiocytosis type 3
    Clin. Immunol. (IF 3.99) Pub Date : 2018-03-26
    Eitaro Hiejima, Hirofumi Shibata, Takahiro Yasumi, Saeko Shimodera, Masayuki Hori, Kazushi Izawa, Tomoki Kawai, Masaki Matsuoka, Yasuko Kojima, Akira Ohara, Ryuta Nishikomori, Osamu Ohara, Toshio Heike

    Familial hemophagocytic lymphohistiocytosis (FHL) type 3 is a life-threatening immune dysregulation syndrome caused by mutations in the UNC13D gene, encoding the munc13–4 protein, which is important for function of cytotoxic lymphocytes. FHL3 accounts for 30–40% of FHL cases, and more than 100 mutations in the UNC13D gene have been described to date. We describe the first case of FHL3 carrying an intragenic duplication of UNC13D, apparently mediated by recombination of Alu elements. NK cell degranulation and munc13–4 protein expression assays are useful for early identification of such mutations, which may be missed by analysis of genomic DNA alone.

    更新日期:2018-03-26
  • Epigenetics as biomarkers in autoimmune diseases
    Clin. Immunol. (IF 3.99) Pub Date : 2018-03-21
    Haijing Wu, Jieyue Liao, Qianwen Li, Ming Yang, Ming Zhao, Qianjin Lu

    Autoimmune diseases are immune system disorders in which immune cells cannot distinguish self-antigens from foreign ones. The current criteria for autoimmune disease diagnosis are based on clinical manifestations and laboratory tests. However, none of these markers shows both high sensitivity and specificity. In addition, some autoimmune diseases, for example, systemic lupus erythematosus (SLE), are highly heterogeneous and often exhibit various manifestations. On the other hand, certain autoimmune diseases, such as Sjogren's syndrome versus SLE, share similar symptoms and autoantibodies, which also causes difficulties in diagnosis. Therefore, biomarkers that have both high sensitivity and high specificity for diagnosis, reflect disease activity and predict drug response are necessary. An increasing number of publications have proposed the abnormal epigenetic modifications as biomarkers of autoimmune diseases. Therefore, this review will comprehensively summarize the epigenetic progress in the pathogenesis of autoimmune disorders and unearth potential biomarkers that might be appropriate for disease diagnosis and prediction.

    更新日期:2018-03-22
  • Phase Ib trial of folate binding protein (FBP)-derived peptide vaccines, E39 and an attenuated version, E39’: An analysis of safety and immune response
    Clin. Immunol. (IF 3.99) Pub Date : 2018-03-21
    Timothy J. Vreeland, Jennifer K. Litton, Na Qiao, Anne V. Philips, Gheath Alatrash, Diane F. Hale, Doreen O. Jackson, Kaitlin M. Peace, Julia M. Greene, John S. Berry, Guy T. Clifton, George E. Peoples, Elizabeth A. Mittendorf

    In this randomized phase Ib trial, we tested combining the E39 peptide vaccine with a vaccine created from E39’, an attenuated version of E39. Patients with breast or ovarian cancer, who were disease-free after standard of care therapy, were enrolled and randomized to one of three arms. Arm EE received six E39 inoculations; arm EE’ received three E39 inoculations followed by three E39’; and arm E’E received three E39’ inoculations, followed by three E39. Within each arm, the first five patients received 500 μg of peptide and the remainder received 1000 μg. Patients were followed for toxicity, and immune responses were measured. This initial analysis after completion of the primary vaccination series has confirmed the safety of both vaccines. Immune analyses suggest incorporating the attenuated version of the peptide improves immune responses and that sequencing of E39 followed by E39’ might produce the optimal immune response. Trial Registration: NCT02019524

    更新日期:2018-03-22
  • TNFAIP3 haploinsufficiency is the cause of autoinflammatory manifestations in a patient with a deletion of 13Mb on chromosome 6
    Clin. Immunol. (IF 3.99) Pub Date : 2018-03-20
    Franco-Jarava Clara, Wang Hongying, Martin-Nalda Andrea, Alvarez de la Sierra Daniel, García-Prat Marina, Bodet Domingo, García-Patos Vicenç, Plaja Alberto, Rudilla Francesc, Rodriguez-Sureda Victor, García-Latorre Laura, Aksentijevich Ivona, Colobran Roger, Soler-Palacín Pere

    There is scarce literature about autoinflammation in syndromic patients. We describe a patient who, in addition to psychomotor and growth delay, presented with fevers, neutrophilic dermatosis, and recurrent orogenital ulcers. Comparative Genomic Hybridization (CGH) array permitted to identify a 13.13Mb deletion on chromosome 6, encompassing 53 genes, and including TNFAIP3 gene (A20). A20 is a potent inhibitor of the NF-kB signalling pathway and restricts inflammation via its deubiquitinase activity. Western blotting and immunoprecipitation assays showed decreased A20 expression and increased phosphorylation of p65 and IkBa. Patient’s cells displayed increased levels of total K63-linked ubiquitin and increased levels of ubiquitinated RIP and NEMO after stimulation with TNF. We describe the molecular characterization of an autoinflammatory disease due to a large chromosomal deletion and review the phenotypes of patients with A20 haploinsufficiency. CGH arrays should be the first diagnostic method for comprehensive analysis of patients with syndromic features and immune dysregulation.

    更新日期:2018-03-20
  • Immunomodulating peptides derived from different human endogenous retroviruses (HERVs) show dissimilar impact on pathogenesis of a multiple sclerosis animal disease model
    Clin. Immunol. (IF 3.99) Pub Date : 2018-03-19
    Shervin Bahrami, Elzbieta Anna Gryz, Jonas Heilskov Graversen, Anne Troldborg, Kristian Stengaard Pedersen, Magdalena Janina Laska

    Retroviruses including Human Endogenous Retroviruses (HERVs), contain a conserved region with highly immunomodulatory functions in the transmembrane proteins in envelope gene (env) named immunosuppressive domain (ISU). In this report, we demonstrate that Env59-GP3 peptide holds therapeutic potential in a mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE). The results show that this specific HERV-H derived ISU peptide, but not peptide derived from another env gene HERV-K, decreased the development of EAE in C57BL/6 mice, accompanied by reduced demyelination and inhibition of inflammatory cells. Moreover, here we tested the effect of peptides on macrophages differentiation. The treatment with Env59-GPS peptide modulate the pro-inflammatory M1 profile and anti-inflammatory M2 macrophages, being shown by inhibiting inflammatory M1 hallmark genes/cytokines expression and enhancing expression of M2 associated markers. These results demonstrate that Env59-GP3 ISU peptide has therapeutic potential in EAE possibly through inducing the polarization of M2 macrophages and inhibiting inflammatory responses.

    更新日期:2018-03-20
  • IPEX due to an exon 7 skipping FOXP3 mutation with autoimmune diabetes mellitus cured by selective TReg cell engraftment
    Clin. Immunol. (IF 3.99) Pub Date : 2018-03-19
    Thomas Magg, Volker Wiebking, Raffaele Conca, Stefan Krebs, Stefan Arens, Irene Schmid, Christoph Klein, Michael H. Albert, Fabian Hauck

    Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare inherited disorder leading to severe organ-specific autoimmunity. IPEX is caused by hemizygous mutations in FOXP3, which codes for a master transcription factor of regulatory T (TReg) cell development and function. We describe a four-year-old boy with typical but slightly delayed-onset of IPEX with autoimmune diabetes mellitus, enteropathy, hepatitis and skin disease. We found the unreported FOXP3 splice site mutation c.816+2T>A that leads to the loss of leucine-zipper coding exon 7. RNA-Seq revealed that FOXP3Δ7 leads to differential expression of FOXP3 regulated genes. After myeloablative conditioning the patient underwent allogeneic HSCT from a matched unrelated donor. HSCT led to the resolution of all IPEX symptoms including insulin requirement despite persisting autoantibody levels. After initial full donor engraftment nearly complete autologous reconstitution was documented, but donor-derived TReg cells persisted with a lineage-specific chimerism of >70% and the patient remained in clinical remission.

    更新日期:2018-03-20
  • Long term outcome of eight patients with type 1 Leukocyte Adhesion Deficiency (LAD-1): Not only infections, but high risk of autoimmune complications
    Clin. Immunol. (IF 3.99) Pub Date : 2018-03-13
    Domenico Umberto De Rose, Silvia Giliani, Lucia Dora Notarangelo, Vassilios Lougaris, Arnalda Lanfranchi, Daniele Moratto, Baldassarre Martire, Fernando Specchia, Alberto Tommasini, Alessandro Plebani, Raffaele Badolato

    Leukocyte Adhesion Deficiency type 1 (LAD-1) is a rare primary immunodeficiency due to mutations in the gene encoding for the common β-chain of the β2 integrin family (CD18). Herein, we describe clinical manifestations and long-term complications of eight LAD-1 patients. Four LAD-1 patients were treated with hematopoietic stem cell transplantation (HSCT), while the remaining four, including two with moderate LAD-1 deficiency, received continuous antibiotic prophylaxis. Untreated patients presented numerous infections and autoimmune manifestations. In particular, two of them developed renal and intestinal autoimmune diseases, despite the expression of Beta-2 integrin was partially conserved. Other two LAD-1 patients developed type 1 diabetes and autoimmune cytopenia after HSCT, suggesting that HSCT is effective for preventing infections in LAD-1, but does not prevent the risk of the autoimmune complications.

    更新日期:2018-03-14
  • Biological therapies in inflammatory bowel disease: Beyond anti-TNF therapies
    Clin. Immunol. (IF 3.99) Pub Date : 2018-03-12
    Konstantinos H. Katsanos, Konstantinos Papamichael, Joseph D. Feuerstein, Dimitrios K. Christodoulou, Adam S. Cheifetz

    The pharmacological management of inflammatory bowel disease (IBD) over the last two decades has transitioned from reliance on aminosalycilates, corticosteroids and immunomodulators to earlier treatment with anti-tumor necrosis factor (anti-TNF) therapy. Nevertheless, 20–30% of patients discontinue anti-TNF therapy for primary non-response and another 30–40% for losing response within one year of treatment. These undesirable therapeutic outcomes can be attributed to pharmacokinetic (anti-drug antibodies and/or low drug concentrations) or pharmacodynamic issues characterized by a non-TNF driven inflammation. The latter issues necessitate the use of medications with different mechanisms of action. Besides the biologics natalizumab, vedolizumab and ustekinumab that have already been approved for the treatment of IBD new non-anti-TNF therapies are currently under investigation including small molecule drugs against Janus kinase and sphingosine-1-phosphate receptors. This manuscript will review the medications that are in the later stages of development for the treatment of IBD and directed against immune targets other than TNF.

    更新日期:2018-03-13
  • Contribution of MTHFR gene variants in lupus related subclinical atherosclerosis
    Clin. Immunol. (IF 3.99) Pub Date : 2018-03-06
    Maira Giannelou, Andrianos Nezos, Sofia Fragkioudaki, Dimitra Kasara, Kyriaki Maselou, Nikolaos Drakoulis, Dimitris Ioakeimidis, Haralampos M. Moutsopoulos, Clio P. Mavragani

    Objective Elevated concentrations of homocysteine have been previously identified as an independent risk factor for subclinical atherosclerosis in patients with systemic lupus erythematosus (SLE). Given that heightened homocysteine levels are known to be strongly influenced by genetic factors, in the current study we investigated the contribution of high homocysteine levels as well as of functional polymorphisms of the gene encoding for the enzyme 5, 10- methylenetetrahydrofolate reductase to atherosclerotic disease characterizing SLE patients. Methods Peripheral DNA samples from 150 SLE patients, 214 rheumatoid arthritis (RA) patients and 561 age/sex matched apparently healthy volunteers (HC) were genotyped by PCR-based assays for the detection of the methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms (c. 677C > T and c. 1298A > C). All SLE patients and 30 age sex matched RA patients underwent assessment for subclinical atherosclerosis [ultrasound measurement of intima-media thickness scores (IMT) and detection of carotid and/or femoral (C/F) plaque] and complete clinical and laboratory evaluation including serum homocysteine levels. Data were analyzed using univariate and multivariate models (SPSS 21.0). Results Hyperhomocysteinemia was detected in 26.0% of SLE patients compared to 6.7% of age/sex matched RA controls (p = 0.02). Higher serum B12 levels and decreased frequency of the MTHFR 677TT variant in RA patients could potentially account for the observed differences between the groups. In SLE patients, both hyperhomocysteinemia and MTHFR677TT genotype were identified as independent contributors for plaque formation, following adjustment for traditional cardiovascular risk factors and disease related features, including age, sex, BMI, cholesterol and triglyceride levels, presence of arterial hypertension, smoking (pack/years), disease duration and total steroid dose [OR 95% (CI): 5.8 (1.0–35.8) and 5.2 (1.1–24.0), respectively]. MTHFR677TT genotype, but not hyperhomocysteinemia was also found to confer increased risk for arterial wall thickening, after the above confounders were taken into account [OR (95%) CI: 4.9 (1.2–20.6)]. Conclusions Hyperhomocysteinemia and MTHFR677TT genetic variant emerged as independent risk factors for subclinical atherosclerosis in SLE patients, implying genetic influences as potential contributors to the increased burden of atherosclerotic disease characterizing SLE.

    更新日期:2018-03-07
  • Epigenetic interplay between immune, stromal and cancer cells in the tumor microenvironment
    Clin. Immunol. (IF 3.99) Pub Date : 2018-03-06
    Antonio Garcia-Gomez, Javier Rodríguez-Ubreva, Esteban Ballestar

    Compelling evidences highlight the critical role of the tumor microenvironment as mediator of tumor progression and immunosuppression in several types of cancer. The reciprocal interplay between neoplastic and non-tumoral host cells is mediated by direct cell-to-cell contact, soluble factors and exosomes that result in differential gene expression patterns that are driven by epigenetic mechanisms. In this regard, extensive literature has described the abnormalities in the DNA methylation status and histone modification profiles in tumor cells. However, little is known about the mechanisms of epigenetic dysregulation that participate as a consequence of the intricate crosstalk among the cells within the tumor niche. This review summarizes the current knowledge on epigenetic changes that result from the interactions between myeloid, stromal and cancer cells in the tumor microenvironment and its functional impact in both tumorigenesis and tumor progression. We also discuss potential niche-specific epigenetic biomarkers to improve the prognosis and clinical treatment of cancer patients.

    更新日期:2018-03-07
  • Reversibility of peripheral blood leukocyte phenotypic and functional changes after exposure to and withdrawal from tofacitinib, a Janus kinase inhibitor, in healthy volunteers
    Clin. Immunol. (IF 3.99) Pub Date : 2018-03-05
    Kent J. Weinhold, Jack F. Bukowski, Todd V. Brennan, Robert J. Noveck, Janet S. Staats, Liwen Lin, Linda Stempora, Constance Hammond, Ann Wouters, Christopher F. Mojcik, John Cheng, Mark Collinge, Michael I. Jesson, Anasuya Hazra, Pinaki Biswas, Shuping Lan, James D. Clark, Jennifer A. Hodge

    This study evaluated the short-term effects of tofacitinib treatment on peripheral blood leukocyte phenotype and function, and the reversibility of any such effects following treatment withdrawal in healthy volunteers. Cytomegalovirus (CMV)-seropositive subjects received oral tofacitinib 10 mg twice daily for 4 weeks and were followed for 4 weeks after drug withdrawal. There were slight increases in total lymphocyte and total T-cell counts during tofacitinib treatment, and B-cell counts increased by up to 26%. There were no significant changes in granulocyte or monocyte counts, or granulocyte function. Naïve and central memory T-cell counts increased during treatment, while all subsets of activated T cells were decreased by up to 69%. T-cell subsets other than effector memory cluster of differentiation (CD)4+, activated naïve CD4+ and effector CD8+ T-cell counts and B-cell counts, normalized 4 weeks after withdrawal. Following ex vivo activation, measures of CMV-specific T-cell responses, and antigen non-specific T-cell-mediated cytotoxicity and interferon (IFN)-γ production, decreased slightly. These T-cell functional changes were most pronounced at Day 15, partially normalized while still on tofacitinib and returned to baseline after drug withdrawal. Total natural killer (NK)-cell counts decreased by 33%, returning towards baseline after drug withdrawal. NK-cell function decreased during tofacitinib treatment, but without a consistent time course across measured parameters. However, markers of NK-cell-mediated cytotoxicity, antibody-dependent cellular cytotoxicity and IFN-γ production were decreased up to 42% 1 month after drug withdrawal. CMV DNA was not detectable in whole blood, and there were no cases of herpes zoster reactivation. No new safety concerns arose. In conclusion, the effect of short-term tofacitinib treatment on leukocyte composition and function in healthy CMV+ volunteers is modest and largely reversible 4 weeks after withdrawal.

    更新日期:2018-03-06
  • Treatment of antiphospholipid syndrome beyond anticoagulation
    Clin. Immunol. (IF 3.99) Pub Date : 2018-03-03
    Chrisanna Dobrowolski, Doruk Erkan

    Antiphospholipid syndrome (APS) is a systemic autoimmune disorder marked by thrombosis and/or pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). At the present time, treatment is primarily focused on anticoagulation. However, there is increasing awareness of the mechanisms involved in APS pathogenesis, which has led to the trial of novel therapies targeting those mechanisms. Following a brief review of the etiopathogenesis of and current management strategies in APS, this paper focuses on the evidence for these potential, targeted APS treatments, e.g., hydroxychloroquine, statins, rituximab, belimumab, eculizumab, defibrotide, sirolimus, and peptide therapy.

    更新日期:2018-03-06
  • Increased risk of hematologic malignancies in primary immunodeficiency disorders: opportunities for immunotherapy
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-27
    Dorit Verhoeven, Arie Jan Stoppelenburg, Friederike Meyer-Wentrup, Marianne Boes

    Primary immunodeficiency disorders (PIDs) convey increased susceptibility to infections and sometimes to malignancies, particularly lymphomas. Such cancer development can be contributed by immune impairments resulting in weakened immunological surveillance against (pre)malignant cells and oncogenic viruses. Molecular defects in PID-patients are therefore being clarified, identifying new targets for innovative immunotherapy. Particularly pediatric cancers are being scrutinized, where over one third of cancer-related deaths is accounted for by leukemia and lymphomas. Here we review how immunopathogenic mechanisms of several PIDs might associate with lymphoma development. We furthermore delineate existing immunotherapy strategies in adults for potential therapeutic application in childhood leukemia and lymphomas.

    更新日期:2018-02-27
  • A novel PADRE-Kv1.3 vaccine effectively induces therapeutic antibodies and ameliorates experimental autoimmune encephalomyelitis in rats
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-27
    Cheng Fan, Rui Long, Ya You, Jue Wang, Xiaofang Yang, Shiyuan Huang, Yuling Sheng, Xu Peng, Hui Liu, Zhaohui Wang, Kun Liu

    Previous studies have confirmed that selective blockade of Kv1.3 channels could modulate the activities of pathogenic T cells and microglia/macrophages, which play key roles in experimental autoimmune encephalomyelitis (EAE). In this study, we designed an anti-Kv1.3 vaccine (PADRE-Kv1.3) to explore its protective role in EAE rat models. When the vaccine was applied in EAE rats, clinical scores and several staining techniques were used to evaluate the severity of the disease. T cell subtypes and related cytokines, as well as microglia/macrophage activation were assayed through flow cytometry, qRT-PCR or immunofluorescence staining, respectively. We herein showed that rats and mice developed high titers of anti-Kv1.3 antibodies and appeared no abnormal manifestations after the PADRE-Kv1.3 vaccine treatment. In EAE models, the vaccine treatment effectively alleviated the clinical severity and lessened pathological damages in the central nervous system (CNS). In addition, we found the vaccine significantly decreased the number of pathogenic T cells (Th17 and IFN-γ–producing T cells) and the production of related pro-inflammatory cytokines (IL-17A, IFN-γ and IL-1β), but increased the number of protective T subsets (CD4+IL-10+ T cells and Treg cells) in the spleen or CNS. Moreover, the infiltration of microglia/macrophages significantly reduced and these cells shifted toward anti-inflammatory M2 subtype in the CNS after the vaccine treatment. Thus, we demonstrated that the PADRE-Kv1.3 vaccine could induce therapeutic anti-Kv1.3 antibodies and ameliorate EAE in rats effectively and safely, which provides a new field of vision for the protection and therapy of multiple sclerosis.

    更新日期:2018-02-27
  • IL10 promoter haplotypes may contribute to altered cytokine expression and systemic inflammation in celiac disease
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-24
    S.R. Hofmann, M.W. Laass, A. Fehrs, D. Schuppan, V.F. Zevallos, D. Salminger, K. Mäbert, C.M. Hedrich

    Celiac disease (CD) is an autoimmune/inflammatory condition triggered by dietary gluten intake in genetically predisposed individuals. Though associations with MHC class II HLA-DQ2 or -DQ8 are the primary and necessary genetic predisposition for CD, >97% of genetically predisposed individuals never develop CD. Cytokines were measured in the serum of CD patients and controls. Possible associations with IL10 promoter variants were investigated. Cytokine expression from PBMCs was monitored in response to gluten exposure, or CD3/TCR complex stimulation in the absence or presence of recombinant IL-10. Serum cytokines varied between patients with CD at the time of diagnosis, after dietary elimination of gluten, and healthy controls. Serum IL-17A reflected disease activity. Reduced IL-10 serum levels and altered IL-10 expression by PBMCs coincided with IL10 promoter haplotypes that encode for “low” IL-10 expression (ATA). Increased prevalence of ATA IL10 promoter haplotypes and subsequently reduced IL-10 expression may be an immunological cofactor in individuals genetically predisposed for the development of CD. Resulting cytokine imbalances may be utilized as disease biomarkers in CD.

    更新日期:2018-02-24
  • Estrogen receptor β activation stimulates the development of experimental autoimmune thyroiditis through up-regulation of Th17-type responses
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-23
    Juan Qin, Li Li, Qian Jin, Dan Guo, Miao Liu, Chenling Fan, Jing Li, Zhongyan Shan, Weiping Teng

    Estrogens play important roles in autoimmune thyroiditis, but it remains unknown which estrogen receptor (ER) subtype (α or β) mediates the stimulatory effects. Herein we treated ovariectomized mice with ERα or ERβ selective agonist followed by thyroglobulin-immunization to induce experimental autoimmune thyroiditis (EAT), and observed the aggravation of EAT after diarylpropionitrile (DPN, ERβ selective agonist) administration. The mRNA levels of interleukin(IL)-17A, IL-21 and RORγt and percentages of T helper (Th) 17 cells were up-regulated in the splenocytes of DPN-treated mice. Activated ERβ was found not only binding to IL-17A and IL-21 gene promoters directly, but also indirectly binding to IL-21 and RORγt gene promoters through interactions with NF-κB. The expressions of co-stimulatory molecules were increased on antigen-presenting cells (APCs), after DPN administration. It suggests that ERβ is the predominant ER subtype responsible for EAT development, and its activation may enhance Th17-type responses through genomic pathways and alteration of APCs' activities.

    更新日期:2018-02-23
  • Progressive severe B cell and NK cell deficiency with T cell senescence in adult CD40L deficiency
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-21
    Vassilios Lougaris, Gaetana Lanzi, Manuela Baronio, Luisa Gazzurelli, Donatella Vairo, Tiziana Lorenzini, Raffaele Badolato, Lucia Dora Notarangelo, Andrea Boschi, Daniele Moratto, Alessandro Plebani

    Highlights • CD40 Ligand deficiency may result in severe B and NK loss over time. • T cell senescence is a novel finding in adult CD40 Ligand deficiency. • Long term follow-up of CD40 Ligand deficiency may reveal novel immunological findings. • CD40 Ligand deficient patients not undergoing HSCT should be closely monitored.

    更新日期:2018-02-21
  • Dysfunction of CD3−CD16+CD56dim and CD3−CD16−CD56bright NK cell subsets in RR-MS patients
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-12
    Ilhan Tahrali, Umut Can Kucuksezer, Ayse Altintas, Ugur Uygunoglu, Nilgun Akdeniz, Esin Aktas Cetin, Gunnur Deniz

    Multiple sclerosis (MS), is a chronic inflammatory disease of central nervous system with unclear etiology. Relapsing-remitting (RR)-MS is the most frequent subtype of disease. Natural Killer (NK) cells have roles in cytotoxicity and immune regulation by cytokine secretions, with uncertain contribution to MS pathogenesis. This study aimed to explore contribution of NK cells to MS pathogenesis. Percentages of CD3−CD16+CD56+ total NK cells, CD3−CD16+CD56dim and CD3−CD16−CD56bright NK cell subsets, NK cytotoxicity and intracellular IFN-γ, IL-10 and IL-22 levels were investigated in patients with RR-MS and clinically isolated syndrome (CIS) as well as healthy subjects. Findings support the possible contribution of NK cells to RR-MS immunopathogenesis. Decreased IFN-γ and increased IL-22 production might have detrimental effects on the clinical course of RR-MS. Impaired cytotoxicity is correlated with disease duration in RR-MS. Moreover, NK cell ratios and EDSS values are negatively correlated in CIS revealing a possible protective role in converting to RR-MS.

    更新日期:2018-02-12
  • Rapamycin attenuates Th2-driven experimental allergic conjunctivitis
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-09
    Soojung Shin, Ji Hyun Lee, Hyun Jung Lee, Sun Young Chang, So-Hyang Chung

    Allergic conjunctivitis is mediated by eosinophilic infiltration and Th2 type immune responses. This study aims to elucidate the role of rapamycin, mTOR inhibitor, on OVA-induced experimental allergic conjunctivitis (EAC). Rapamycin administration intraperitoneally markedly reduced clinical signs, total and OVA-specific IgE and IgG1/G2a ratio in serum, and conjunctival eosinophilic infiltration. Infiltrations of CD11c+ dendritic cells and CD4+ T cells, and the expressions of chemokines and adhesion molecules in the conjunctiva were attenuated in rapamycin-treated mice, as well as decreased Th1 and Th2 cytokines in the cervical lymph nodes compared to non-treated mice. The expression of mTOR signaling proteins was increased in EAC and reduced by rapamycin treatment. Topical application of rapamycin was also proved to show reduced clinical signs, eosinophil infiltration, and Th2 type immune responses comparable to those from intraperitoneal injection of rapamycin. These findings suggest the therapeutic implications of rapamycin in the attenuation of allergic conjunctivitis.

    更新日期:2018-02-10
  • Mechanistic aspects of epigenetic dysregulation in SLE
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-06
    Christian Michael Hedrich

    Epigenetic events have been linked with disease expression in individuals genetically predisposed to the development of systemic lupus erythematosus (SLE), a severe systemic autoimmune/inflammatory disease. Altered DNA methylation and hydroxymethylation as well as histone modifications mediate changes in chromatin accessibility and gene expression in immune cells from SLE patients. Defective epigenetic control contributes to uncontrolled expression of inflammatory mediators, including cytokines and co-receptors, resulting in systemic inflammation and tissue damage. While the pathophysiological involvement of epigenetic changes in SLE has been accepted for some time, we only recently started to investigate and understand molecular events contributing to epigenetic dysregulation. Here, epigenetic alterations will be discussed with a focus on underling molecular events that may be target of preventative measures or future treatment strategies.

    更新日期:2018-02-07
  • Diminished antibody response to influenza vaccination is characterized by expansion of an age-associated B-cell population with low PAX5
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-06
    Allison J. Nipper, Megan J. Smithey, Raj C. Shah, David H. Canaday, Alan L. Landay

    Individuals over the age of 65 comprise a substantial portion of the world population and become more susceptible to vaccine-preventable infections with age as vaccination response diminishes. The underlying reason for this impaired vaccine response in older individuals is not entirely clear. We evaluated potential differences in phenotypic and functional responses of B cells from healthy younger (22–45 years) and older (64–95 years) individuals that may associate with a diminished antibody response to influenza vaccination. We report that age is associated with expansion of atypical memory B cells (CD10−CD20+CD21−CD27−) and an age-associated B cell (ABC, CD21−T-bet+CD11c+) phenotype. Reduced expression of PAX5 was also seen in older individuals. Poor influenza-specific antibody production following vaccination was associated with low PAX5 expression and a distinct composition of the ABC compartment. Collectively, these findings demonstrate that the characteristics of the ABC populations of older individuals are associated with antibody production following influenza vaccination.

    更新日期:2018-02-07
  • Epigenetic editing: How cutting-edge targeted epigenetic modification might provide novel avenues for autoimmune disease therapy ☆
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-06
    Matlock A. Jeffries

    Autoimmune diseases are enigmatic and complex, and most been associated with epigenetic changes. Epigenetics describes changes in gene expression related to environmental influences mediated by a variety of effectors that alter the three-dimensional structure of chromatin and facilitate transcription factor or repressor binding. Recent years have witnessed a dramatic change and acceleration in epigenetic editing approaches, spurred on by the discovery and later development of the CRISPR/Cas9 system as a highly modular and efficient site-specific DNA binding domain. The purpose of this article is to offer a review of epigenetic editing approaches to date, with a focus on alterations of DNA methylation, and to describe a few prominent published examples of epigenetic editing. We will also offer as an example work done by our laboratory demonstrating epigenetic editing of the FOXP3 gene in human T cells. Finally, we discuss briefly the future of epigenetic editing in autoimmune disease.

    更新日期:2018-02-06
  • Impaired X-CGD T cell compartment is gp91phox-NADPH oxidase independent
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-03
    Maria Chiriaco, Fabio Casciano, Gigliola Di Matteo, Berhard Gentner, Alessia Claps, Nicola Cotugno, D'. Argenio Patrizia, Paolo Rossi, Alessandro Aiuti, Andrea Finocchi

    Chronic granulomatous disease (CGD) is a phagocytic disorder characterized by a defective production of reactive oxygen species (ROS). Although infections and granuloma formation are the most common manifestations in CGD patients, a significant number of patients experienced autoimmunity and inflammatory diseases suggesting that adaptive immune abnormalities might be involved. Here we investigated T-cell compartment and showed that CGD patients respect to healthy donor (HD), had a skewed TCRV-beta distribution in CD8+ T cells, particularly in older patients, and a reduced proliferative responses toward mitogens. Afterwards we studied the role of gp91phox protein in causing these alterations and demonstrated that human T cells do not express gp91phox and TCR-stimulated ROS generation is gp91phox-NADPH oxidase independent. Finally, we proved that the NADPH oxidase is not active in the T cell compartment even forcing gp91phox expression transducing T cells from X-CGD and HD with a SIN lentiviral vector (LVV) expressing the gp91phox cDNA.

    更新日期:2018-02-04
  • Citrullinated fibrinogen impairs immunomodulatory function of bone marrow mesenchymal stem cells by triggering toll-like receptor
    Clin. Immunol. (IF 3.99) Pub Date : 2018-01-31
    Yue Sun, Wei Deng, Genhong Yao, Weiwei Chen, Xiaojun Tang, Xuebing Feng, Liwei Lu, Lingyun Sun

    Bone marrow mesenchymal stem cells (BMSC) have been shown to possess immunomodulatory activities, while its role in rheumatoid arthritis (RA) remains unknown. Citrullinated fibrinogen (cfb) has been considered as a specific autoantigen in RA pathogenesis. Our study aims to determine the role of cfb on immunomodulatory function of BMSC. We demonstrated the specific role of toll-like receptor 4 (TLR4)-NFκB pathway in the pro-inflammatory response of BMSC to cfb with increased production of interleukin (IL)-6, IL-8 and chemokine C single bond C motif ligand 2 (CCL2). Moreover, cfb impaired BMSC-mediated suppression of peripheral blood mononuclear cells (PBMC) proliferation and reduced the production of the key immunomodulatory molecule indoleamine 2,3-dioxygenase (IDO) in BMSC. We have uncovered a previously unrecognized role of cfb in interfering BMSC-mediated immunoregulation in RA. Cfb could act as a damage-associated molecule pattern (DAMP) for BMSC and thereby contribute to the propagation of inflammation in RA.

    更新日期:2018-02-02
  • Thymopoiesis following HSCT; a retrospective review comparing interventions for aGVHD in a pediatric cohort
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-01
    A.M. Flinn, C.F. Roberts, M.A. Slatter, R. Skinner, H. Robson, J. Lawrence, J. Guest, A.R. Gennery

    Acute graft-versus-host disease (aGVHD) complicates allogeneic hematopoietic stem cell transplantation (HSCT), and is treated with topical and/or systemic corticosteroids. Systemic corticosteroids and aGVHD damage thymic tissue. We compared thymopoietic effect of topical steroid therapy, corticosteroids and extracorporeal photopheresis (ECP) in 102 pediatric allogeneic HSCT patients. We categorized patients into 4 groups: - no aGVHD, aGVHD treated with topical or systemic steroid, or ECP. Naïve CD4+ CD45RA+ CD27+ T-lymphocyte values at 3, 6, 9, 12 months post-HSCT were recorded: for ECP patients, values were recorded at 3, 6, 9, 12 months during ECP. Differences were compared using the Kruskal-Wallis test. 41 patients had no aGVHD, 23 had aGVHD treated topically or systemically (25), 13 received ECP. Rate of thymopoiesis was significantly different between all groups at all time-points post-transplant (p = 0.002, p < 0.001, p < 0.001, p = 0.001 respectively). Even mild aGVHD impairs thymopoiesis. Worst recovery was in ECP patients. Earlier institution of ECP may speed thymic recovery.

    更新日期:2018-02-02
  • Cisplatin inhibits the progression of bladder cancer by selectively depleting G-MDSCs: A novel chemoimmunomodulating strategy
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-02
    Ke Wu, Ming-Yue Tan, Jun-Tao Jiang, Xing-Yu Mu, Jie-Ren Wang, Wen-Jie Zhou, Xiang Wang, Ming-qing Li, Yin-Yan He, Zhi-Hong Liu

    Bladder cancer (BC) is a disease arising from the malignant cells of the urinary bladder. Myeloid-derived suppressor cells (MDSCs) expand broadly and have strong immunosuppressive activities in the cancer microenvironment. Determining how to inhibit the negative effects of MDSCs requires immediate attention. In this study, we found that granulocytic-MDSCs (G-MDSCs), which constitute one of the two types of MDSCs, were significantly increased in BC tissues compared with those in the adjacent bladder tissues. There was a robust negative correlation between the G-MDSCs and the CD8+ T cells in the BC tissues. In this study, we attempted to identify pharmacological approaches to eliminate MDSCs and restore T cell anti-tumor activities. It is necessary to explore a method to eliminate the detrimental effects of MDSCs. Cisplatin, a chemotherapy medication used to treat BC, not only rapidly kills proliferating cancer cells but also affects the tumor immune microenvironment. However, the mechanism underlying this phenomenon is largely unknown. In this study, we found that Cisplatin directly inhibited the proliferation and induced the apoptosis of T24 cells (a BC cell line), as well as decreased the percentage of the G-MDSCs in the population of peripheral blood mononuclear cells (PBMCs), which restored the expansion of the CD8+ T cells. In the C3H/He mouse BC model, Cisplatin treatment inhibited the progression of BC and effectively decreased the proportion of G-MDSCs. These results suggest that Cisplatin treatment enhances the anti-tumor function of CD8+ T cells by decreasing G-MDSCs. This finding provides a new perspective for Cisplatin treatment to prevent the progression of BC, particularly in patients with abnormally high levels of G-MDSCs.

    更新日期:2018-02-02
  • Plasmablast antibody repertoires in elderly influenza vaccine responders exhibit restricted diversity but increased breadth of binding across influenza strains
    Clin. Immunol. (IF 3.99) Pub Date : 2018-02-02
    Chia-Hsin Ju, Lisa K. Blum, Sarah Kongpachith, Nithya Lingampalli, Rong Mao, Petter Brodin, Cornelia L. Dekker, Mark M. Davis, William H. Robinson

    Seasonal influenza vaccines elicit antibody responses that can prevent infection, but their efficacy is reduced in the elderly. While a subset of elderly individuals can still mount sufficient vaccine-induced antibody responses, little is known about the properties of the vaccine-induced antibody repertoires in elderly as compared to young responders. To gain insights into the effects of aging on influenza vaccine-induced antibody responses, we used flow cytometry and a cell-barcoding method to sequence antibody heavy and light chain gene pairs expressed by individual blood plasmablasts generated in response to influenza vaccination in elderly (aged 70–89) and young (aged 20–29) responders. We found similar blood plasmablast levels in the elderly and young responders seven days post vaccination. Informatics analysis revealed increased clonality, but similar heavy chain V(D)J gene usage in the elderly as compared to young vaccine responders. Although the elderly responders exhibited decreased antibody sequence diversity and fewer consequential mutations relative to young responders, recombinant antibodies from elderly responders bound a broader range of influenza strain HAs. Thus elderly influenza vaccine responders mount plasmablast responses with restricted diversity but with an increased breadth of binding across influenza strains. Our results suggest that the ability to generate plasmablast responses encoding cross-strain binding antibodies likely represents a mechanism important to vaccine responses in the elderly.

    更新日期:2018-02-02
  • Human CD4+ CD25+ CD127hi cells and the Th1/Th2 phenotype
    Clin. Immunol. (IF 3.99) Pub Date : 2018-01-10
    Aditi Narsale, Rosita Moya, Joanna Davida Davies

    CD4+ T cells that co-express CD25 and CD127 (CD25+ CD127+) make up around 20% of all circulating CD4+ memory T cells in healthy people. The clinical significance of these cells is that in children with type 1 diabetes their relative frequency at diagnosis is significantly and directly correlated with rate of disease progression. The purpose of this study was to further characterize the CD25+ CD127hi cells. We show that they are a mix of Th1 and Th2 cells however, they have a significantly higher relative frequency of pre-committed and committed Th2 cells, and secrete significantly higher levels of Th2-type cytokines than CD25− memory T cells. Further, these cells are neither exhausted nor senescent and proliferate to the same extent as CD25− memory cells. Thus, CD25+ CD127hi cells are a highly active subset of memory T cells that might play a role in controlling inflammation via anti-inflammatory Th2-type deviation.

    更新日期:2018-01-10
  • Pediatric-onset Evans syndrome: Heterogeneous presentation and high frequency of monogenic disorders including LRBA and CTLA4 mutations
    Clin. Immunol. (IF 3.99) Pub Date : 2018-01-10
    Caroline Besnard, Eva Levy, Nathalie Aladjidi, Marie-Claude Stolzenberg, Aude Magerus-Chatinet, Olivier Alibeu, Patrick Nitschke, Stéphane Blanche, Olivier Hermine, Eric Jeziorski, Judith Landman-Parker, Guy Leverger, Nizar Mahlaoui, Gérard Michel, Isabelle Pellier, Felipe Suarez, Isabelle Thuret, Geneviève de Saint-Basile, Capucine Picard, Alain Fischer, Bénédicte Neven, Frédéric Rieux-Laucat, Pierre Quartier

    Evans syndrome (ES) is defined by the combination of autoimmune hemolytic anemia and immune thrombocytopenia. Clinical presentation includes manifestations of immune dysregulation, found in primary immune deficiencies, autoimmune lymphoproliferative syndrome with FAS (ALPS-FAS), Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) and Lipopolysaccharide-Responsive vesicle trafficking Beige-like and Anchor protein (LRBA) defects. We report the clinical history and genetic results of 18 children with ES after excluding ALPS-FAS. Thirteen had organomegaly, five lymphocytic infiltration of non-lymphoid organs, nine hypogammaglobulinemia and fifteen anomalies in lymphocyte phenotyping. Seven patients had genetic defects: three CTLA4 mutations (c.151C > T; c.109 + 1092_568-512del; c.110-2A > G) identified by Sanger sequencing and four revealed by Next Generation Sequencing: LRBA (c.2450 + 1C > T), STAT3 gain-of-function (c.2147C > T; c.2144C > T) and KRAS (c.37G > T). No feature emerged to distinguish patients with or without genetic diagnosis. Our data on pediatric-onset ES should prompt physicians to perform extensive screening for mutations in the growing pool of genes involved in primary immune deficiencies with autoimmunity.

    更新日期:2018-01-10
  • A young girl with severe cerebral fungal infection due to card 9 deficiency
    Clin. Immunol. (IF 3.99) Pub Date : 2018-01-04
    Pinar Gur Cetinkaya, Deniz Cagdas Ayvaz, Betül Karaatmaca, Rahsan Gocmen, Figen Söylemezoğlu, Wayne Bainter, Janet Chou, Talal A. Chatila, Ilhan Tezcan

    Pattern recognition receptors (PRRs), receptors of the innate immune system, are important in interaction with pathogens. Caspase Recruitment Domain-containing protein 9 (CARD9), a member of PRRs, is an intracellular adaptor protein important in fungal defense. CARD9 deficiency causes a rare primary immunodeficiency (PID) characterized by superficial and deep fungal infections. We report a 17 year-old female with a homozygous nonsense mutation in CARD9, who presented with severe cerebral fungal infection of the central nervous system. She was also found to have an heterozygous NLRP12 mutation, which may have had add-on effect on the severity of the infection.

    更新日期:2018-01-04
  • Study of an extended family with CTLA-4 deficiency suggests a CD28/CTLA-4 independent mechanism responsible for differences in disease manifestations and severity
    Clin. Immunol. (IF 3.99) Pub Date : 2018-01-03
    Tie Zheng Hou, Peter Olbrich, Jose Manuel Lucena Soto, Berta Sanchez, Paula Sanchez Moreno, Stephan Borte, Hans J. Stauss, Siobhan O. Burns, Lucy S.K. Walker, Qiang Pan-Hammarström, Lennart Hammarström, David M. Sansom, Olaf Neth

    The CTLA-4 checkpoint regulates the activation of T cells. Individuals with heterozygous mutations in CTLA-4 have a complex phenotype typically characterized by antibody deficiency alongside variable autoimmunity. Despite severe disease in some individuals, others remain largely unaffected with reasons for this variation unknown. We studied a large family carrying a single point mutation in CTLA-4 leading to an amino acid change R75W and compared both unaffected with affected individuals. We measured a variety of features pertaining to T cell and CTLA-4 biology and observed that at the cellular level there was complete penetrance of CTLA-4 mutations. Accordingly, unaffected individuals were indistinguishable from those with disease in terms of level of CTLA-4 expression, percentage of Treg, upregulation of CTLA-4 upon stimulation and proliferation of CD4 T cells. We conclude that the wide variation in disease phenotype is influenced by immune variation outside of CTLA-4 biology.

    更新日期:2018-01-04
  • Investigation of autoantibodies to SP-1 in Chinese patients with primary Sjögren's syndrome
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-29
    Jingxiu Xuan, Ying Wang, Yinglin Xiong, Hongyan Qian, Yan He, Guixiu Shi

    In order to evaluate autoantibody to SP-1 as an early biomarker in pSS, we investigated autoantibody to SP-1 in Chinese patients with primary Sjögren's syndrome (pSS). Autoantibodies to SP-1 are significantly increased in pSS patients compared to RA patients, SLE patients, and healthy people without secondary SS. The presence of anti SP-1 antibodies was negatively correlated with the focus score (FS), RF, and salivary gland function. It was positively correlated with FS = 0, RF ≤ 20, and normal salivary gland function. In further studies, the autoantigen SP-1 was identified in ductal epithelia of salivary glands in il14α TG mice by IIF. SP-1 mRNAs expression increased with growing age in il14α TG mice. SP-1 mRNA was also identified in labial biopsies of patients with pSS. In conclusion, autoantibody to SP-1 is an early marker in pSS. It is useful to diagnose pSS patients who lack RF or antibodies to Ro/La.

    更新日期:2017-12-31
  • A novel bivalent fusion vaccine induces broad immunoprotection against Staphylococcus aureus infection in different murine models
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-28
    Liuyang Yang, Heng Zhou, Ping Cheng, Yun Yang, Yanan Tong, Qianfei Zuo, Jiao Luo, Qiang Feng, Quanming Zou, Hao Zeng

    With more and more drug-resistant Staphylococcus aureus strains emerging in hospitals, there is an urgent need to develop an effective vaccine to combat S. aureus infection. In this study, we constructed a novel bivalent fusion vaccine, SpA-DKKAA-FnBPA37-507 (SF), based on the D domain of staphylococcal protein A (SpA) and the A domain of fibronectin-binding protein A (FnBPA). Immunisation with SF induced a more ideal protective effect compared with the single components alone in a sepsis model. It also showed broad immunoprotection against seven FnBPA isotypes. Vaccination with SF induced strong antibodies responses and Th1/Th17 polarized cellular responses. Further we demonstrated the protective effect of antibodies by the opsonophagocytic assay (OPA) and passive immunisation. Moreover, vaccination with SF showed protective efficacy in a murine pneumonia model and skin abscess model. These results suggest that SF can be regarded as a promising vaccine candidate for the prevention of S. aureus infections.

    更新日期:2017-12-31
  • Effect of glucocorticoid treatment on BAFF and APRIL expression in patients with immune thrombocytopenia (ITP)
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-26
    Julian Kamhieh-Milz, Nuha Ghosoun, Viktor Sterzer, Abdulgabar Salama

    Immune thrombocytopenic purpura (ITP) is an idiopathic bleeding disorder. B cell activating factor (BAFF) and ‘A proliferation-inducing ligand’ (APRIL) have regulatory effects on B and T cells and may represent relevant factors in the pathogenesis of ITP. Serum levels and gene expression were investigated in ITP patients. Both BAFF and APRIL serum levels were significantly elevated in active ITP. However, gene expression analysis revealed both factors to have a tendency toward downregulation. Glucocorticoid treatment significantly reduced BAFF but not APRIL serum levels, which may be mediated by differences in transcription factor binding sites. The glucocorticoid receptor binding site is present in the BAFF promotor region, but not in the APRIL promotor region. Prednisolone in combination with vitamin D3 may be effective in reducing APRIL serum levels. In conclusion, glucocorticoid treatment exerts different regulatory effects on both BAFF and APRIL, whereas antioxidant supplementation may also be beneficial in reducing serum levels.

    更新日期:2017-12-27
  • IL-21 dependent Granzyme B production of B-cells is decreased in patients with lupus nephritis
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-21
    Mariam Rabani, Benjamin Wilde, Katharina Hübbers, Shilei Xu, Andreas Kribben, Oliver Witzke, Sebastian Dolff

    Objectives B-cells play a crucial role in the pathogenesis of lupus nephritis. Recently, a separate subset has been discovered characterized by expression of Granzyme B. The aim of this study is to investigate this subset in patients with systemic lupus erythematosus (SLE). Methods Isolated PBMCs of SLE-patients (n = 30) and healthy controls (n = 21) were in vitro stimulated with CPG, IgG + IgM and IL-21. Patients were sub-grouped in patients with and without biopsy proven lupus nephritis. B-cells were analyzed for intracellular Granzyme B expression by flow cytometry. Results The strongest stimulus for Granzyme B secretion of B-cells was IgG + IgM in presence of IL-21. SLE-patients had a significant decreased percentage of Granzyme B+ B-cells in particular SLE-patients with active disease and with lupus nephritis. Conclusions The frequency of GrB + producing B-cells is reduced in SLE patients. This may contribute to an imbalanced B-cell regulation towards effector B-cells which might promote the development of lupus nephritis.

    更新日期:2017-12-21
  • Extracellular ATP signaling and clinical relevance
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-20
    Lei Dou, Yi-Fa Chen, Peter J. Cowan, Xiao-ping Chen

    Since purinergic signaling was discovered in the early 1970s, it has been shown that extracellular nucleotides, and their derivative nucleosides, are released in a regulated or unregulated manner by cells in various challenging settings and then bind defined purinergic receptors to activate intricate signaling networks. Extracellular ATP plays a role based on different P2 receptor subtypes expressed on specific cell types. Sequential hydrolysis of extracellular ATP catalyzed by ectonucleotidases (e.g. CD39, CD73) is the main pathway for the generation of adenosine, which in turn activates P1 receptors. Many studies have demonstrated that extracellular ATP signaling functions as an important dynamic regulatory pathway to coordinate appropriate immune responses in various pathological processes, including intracellular infection, host-tumor interaction, pro-inflammation vascular injury, and transplant immunity. ATP receptors and CD39 also participate in related clinical settings. Here, we review the latest research in to the development of promising clinical treatment strategies.

    更新日期:2017-12-21
  • Modulation the expression of natural killer cell activating receptor (NKp44) in the peripheral blood of diffuse large B-cell lymphoma patients and the correlation with clinic pathological features
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-13
    Enas Said Essa, Gehan Abd-Elfatah Tawfeek, Suzan Ahmed El Hassanin, Khloud Gamal Mohammed Emara

    NK cell activation is one strategy to improve the immunotherapy of non-Hodgkin's lymphoma. So, we aimed to investigate expression of Natural killer cell activating receptor NKp44 in patients with diffuse large B-cell lymphoma (DLBCL) and its correlation with clinic pathological data. In this study, 30 new cases with DLBCL in addition to 20 healthy control were involved. All were submitted to full history, clinical examination, histopathology, Routine laboratory investigations including CBC, LDH, β2microgloubine and bone marrow examination. Cell culture of peripheral blood mononuclear cells and expression of CD56 and NKp44 by flowcytometry was done. We demonstrated increased NK cell populations (CD 56 + ve NKp44 –ve, CD 56 –veNKp44 + ve, total CD 56 + ve) and NKp44 MFI after in-vitro activation in both healthy control and DLBCL cases except for CD 56 + ve NKp44 + ve which significantly increased in patients not in healthy control (p = 0.005, 0.601) respectively. No significant difference between the DLBCL and healthy control regarding all NK cell populations without PHA stimulation. However, the culture with PHA in DLBCL showed significant increase in NK cell populations than the healthy control (CD 56 + ve NKp44 + ve 12.37 ± 7.52vs 6.80 ± 4.07, p = 0.008), (Total CD 56 + ve 18.80 ± 8.74vs 12.66 ± 5.17, p = 0.017), (MFI of NKp44 10.95 ± 6.18vs 5.58 ± 1.70, p = 0.001). Regarding the association with clinic pathologic features, increased expression of NKp44 was associated with lower values of LDH and earlier stages of DLBCL (p < 0.05). So, activating receptor NKp44 can be modulated by in-vitro activation, hence improvement of its function as an approach of immunotherapy of DLBCL.

    更新日期:2017-12-14
  • Altered natural killer cell cytokine profile in type 2 autoimmune hepatitis
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-09
    Dalila Mele, Grazia Bossi, Giuseppe Maggiore, Barbara Oliviero, Stefania Mantovani, Beatrice Bonelli, Mario U. Mondelli, Stefania Varchetta
    更新日期:2017-12-14
  • GM-CSF producing autoreactive CD4+ T cells in type 1 diabetes
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-08
    Jan Knoop, Anita Gavrisan, Denise Kuehn, Julia Reinhardt, Melanie Heinrich, Markus Hippich, Anne Eugster, Christian Ockert, Anette-Gabriele Ziegler, Ezio Bonifacio

    The phenotype of autoreactive T cells in type 1 diabetes is described as Th1, Th17 and/or Th21, but is largely uncharacterized. We combined multi-parameter cytokine profiling and proliferation, and identified GM-CSF producing cells as a component of the response to beta cell autoantigens proinsulin and GAD65. Overall cytokine profiles of CD4 + T cell were not altered in type 1 diabetes. In contrast, patients with recent onset type 1 diabetes had increased frequencies of proinsulin-responsive CD4 + CD45RA- T cells producing GM-CSF (p = 0.002), IFNγ (p = 0.004), IL-17A (p = 0.008), IL-21 (p = 0.011), and IL-22 (p = 0.007), and GAD65-responsive CD4 + CD45RA- T cells producing IL-21 (p = 0.039). CD4 + T cells with a GM-CSF + IFNγ-IL-17A-IL-21-IL-22- phenotype were increased in patients for responses to both proinsulin (p = 0.006) and GAD65 (p = 0.037). GM-CSF producing T cells are a novel phenotype in the repertoire of T helper cells in type 1 diabetes and consolidate a Th1/Th17 pro-inflammatory pathogenesis in the disease.

    更新日期:2017-12-14
  • Chronic Granulomatous Disease in children: a single center experience
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-07
    Alessandra Beghin, Marta Comini, Annarosa Soresina, Luisa Imberti, Michela Zucchi, Alessandro Plebani, Alessandro Montanelli, Fulvio Porta, Arnalda Lanfranchi

    Chronic Granulomatous Disease (CGD) is caused by the failure of the phagocytes to kill pathogens. We carried out a retrospective analysis of cellular, molecular and clinical features of 14 young patients (mean age at the onset of symptoms and diagnosis: 10 and 25 months, respectively), 7 with autosomal recessive and 7 X-linked form, referred to the Children's Hospital of Brescia between 1999 and 2016. Two new mutations were found, one localized in the CYBB and one in the NCF1 genes. Twelve patients were followed in our institution; the average length of their follow-up after diagnosis was 66 months in X-linked patients and 126 months in autosomal recessive inheritance. The overall survival was 67%, 40% in X-linked and 86% in autosomal recessive form. Eight patients were treated with HSCT. We did not find a clear correlation between the clinical symptoms and the type of mutation, but the fine characterization of the patients was mandatory for therapeutic option, genetic counseling and prenatal diagnosis.

    更新日期:2017-12-14
  • STAT3-mediated epigenetic silencing of FOXP3 in LADA T cells is regulated through HDAC5 and DNMT1
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-06
    Can Hou, Yanjun Zhong, Zhen Wang, Zhao Ming, Gan Huang, Lin Ouyang, Yijun Li, Qianjin Lu, Zhiguang Zhou

    In LADA patients, Tregs are reduced and FOXP3 is downregulated in CD4+ T cells, but the etiology remains unclear. Our study included in 20 LADA patients and 20 healthy control patients. qRT-PCR results showed that STAT3, HDAC3, HDAC5, SIRT1, DNMT1 and DNMT3b mRNAs were significantly upregulated in LADA CD4+ T cells than controls, while FOXP3 mRNA significantly decreased. p-STAT3, STAT3, DNMT1 and DNMT3b expressions were increased demonstrated by western blot. ChIP-PCR suggested that p-STAT3 binds to the Foxp3 promoter, meanwhile, histone H3 acetylation at K9 and K14 of FOXP3 promoter were significantly lower than controls. Luciferase reporter assay showed that ectopic STAT3 expression significantly reduced FOXP3 promoter activities. The Foxp3 promoter was significantly hypermethylated in LADA than controls. LADA patients showed stronger binding of p-STAT3, HDAC5 and DNMT1 than controls using CHIP. These findings reveal a crucial role of STAT3 in regulating the epigenetic status of T cells in LADA.

    更新日期:2017-12-14
  • Up-regulation of chemokine CXCL13 in systemic candidiasis
    Clin. Immunol. (IF 3.99) Pub Date : 2017-12-01
    Congya Li, Ju Cao, Lifang Wang, Xiaojiong Jia, Jianchun He, Liping Zhang

    Candida albicans is the leading cause of healthcare associated bloodstream infections. Chemokine CXCL13 is well-known involved in inflammation, but its role in candidemia has not been assessed. Our study firstly demonstrated that serum CXCL13 levels were significantly elevated in candidemic patients compared with bacteremic patients and control subjects by ELISA, and CXCL13 concentrations were positively and significantly correlated with clinical Sequential Organ Failure Assessment (SOFA) scores and several laboratory parameters in patients. Moreover, ROC curve analysis showed the diagnostic efficiency of CXCL13 was superior to CRP and PCT. To further study the role of CXCL13, a mouse model was established. Importantly, the data showed the dramatically elevated levels of CXCL13 in mice serum and infected kidney, were significantly correlated with renal fungal burden and pathology scores. In conclusion, our results indicated that CXCL13 had strong potential as a novel biomarker of diagnosis and prognosis for candidemia.

    更新日期:2017-12-14
  • Subcutaneous immunoglobulins in patients with multiple myeloma and secondary hypogammaglobulinemia
    Clin. Immunol. (IF 3.99) Pub Date : 2017-11-28
    Angelo Vacca, Carolina Marasco, Assunta Melaccio, Azzurra Sportelli, Ilaria Saltarella, Antonio Solimando, Franco Dammacco, Roberto Ria

    Multiple myeloma is commonly associated with a reduction of non-paraprotein immunoglobulins, resulting in a higher risk of infections that represent the leading cause of the patients' death. Therefore, immunoglobulin replacement therapy appears a logical approach. A total number of 46 myeloma patients were enrolled: 24 of them were assigned to receive subcutaneous immunoglobulins, and 22 were controls. The primary endpoint was the evaluation of the annual rate of severe infections in immunoglobulins-receiving patients as compared with those untreated. Subcutaneous immunoglobulins-treated patients showed a significantly lower number of severe infections per year. Adverse events were limited to the site of infusion and were easily manageable. Health-related quality of life was significantly better in subcutaneous immunoglobulins-receiving patients. By decreasing the rate of infections, the prophylactic administration of SCIg improves both adherence to chemotherapy and health-related quality of life, and is cost-effective by reducing the need of hospitalization and the use of antibiotics.

    更新日期:2017-12-14
  • Circulating IL-17-producing mucosal-associated invariant T cells (MAIT) are associated with symptoms in children with asthma
    Clin. Immunol. (IF 3.99) Pub Date : 2017-11-28
    Guillaume Lezmi, Rola Abou Taam, Céline Dietrich, Lucienne Chatenoud, Jacques de Blic, Maria Leite-de-Moraes

    IL-17 and mucosal-associated invariant T (MAIT) cells have been involved in asthma pathogenesis. However, IL-17-producing MAIT cells (MAIT-17) were not evidenced. We aimed to determine whether circulating MAIT-17 were detectable in children with asthma, and whether they correlated with asthma symptoms or lung function. Children from the SPASM cohort of preschoolers with severe wheeze were reassessed for asthma at school age, and categorized as exacerbators (1 or more severe exacerbations in the previous 12 months) or non-exacerbators. Nineteen children (10.9 years) were included (9 non-exacerbators, 10 exacerbators). Circulating MAIT-17 were detected by flow cytometry. Their frequency was higher in exacerbators than in non-exacerbators (1.9 [1.01–3.55] vs 0.58 [0.46–1.15], p < 0.01). MAIT-17 correlated with the number of severe exacerbations (r = 0.68, p < 0.001), and correlated negatively with the ACT score (r = − 0.55, p = 0.01). In summary, MAIT-17 are present in children with asthma and associated with asthma symptoms.

    更新日期:2017-12-14
  • An optimized whole blood assay measuring expression and activity of NLRP3, NLRC4 and AIM2 inflammasomes
    Clin. Immunol. (IF 3.99) Pub Date : 2017-11-26
    Lev Grinstein, Hella Luksch, Felix Schulze, Avril A.B. Robertson, Matthew A. Cooper, Angela Rösen-Wolff, Stefan Winkler

    The proinflammatory protease caspase-1 plays pivotal roles in central pathways of innate immunity, thereby contributing to pathogen clearance. Beside its physiological role, dysregulated activity of caspase-1 is known to contribute to an increasing number of diseases. In this study we optimized and validated a low-volume human whole blood assay facilitating the measurement of caspase-1 activation and inflammasome-related gene expression upon stimulation of the NLRP3, NLRC4 or AIM2 inflammasome. Using the NLRP3 inflammasome specific inhibitor MCC950 we were able to measure the activity of canonical or alternative NLRP3 pathways, AIM2 and NLRC4 inflammasomes in whole blood. Based on our data we assume a superposition of NLRP3 and NLRC4 inflammasome activities in human whole blood following stimulation with S. typhimurium. The optimized whole blood assay may be suitable for diagnostic and research purposes for pediatric patients who can only donate small amounts of blood.

    更新日期:2017-12-14
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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