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Clinical Immunology: the Official Journal of the Clinical Immunology Society

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https://www.readbyqxmd.com/read/28223071/therapeutic-antibody-targeting-of-indoleamine-2-3-dioxygenase-ido2-inhibits-autoimmune-arthritis
#1
Lauren M F Merlo, Samantha Grabler, James B DuHadaway, Elizabeth Pigott, Kaylend Manley, George C Prendergast, Lisa D Laury-Kleintop, Laura Mandik-Nayak
Rheumatoid arthritis (RA) is a debilitating inflammatory autoimmune disease with no known cure. Recently, we identified the immunomodulatory enzyme indoleamine-2,3-dioxygenase 2 (IDO2) as an essential mediator of autoreactive B and T cell responses driving RA. However, therapeutically targeting IDO2 has been challenging given the lack of small molecules that specifically inhibit IDO2 without also affecting the closely related IDO1. In this study, we develop a novel monoclonal antibody (mAb)-based approach to therapeutically target IDO2...
February 18, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28216420/evaluation-of-rag1-mutations-in-an-adult-with-combined-immunodeficiency-and-progressive-multifocal-leukoencephalopathy
#2
Claudia Schröder, Niklas Baerlecken, Ulrich Pannicke, Thilo Dörk, Torsten Witte, Roland Jacobs, Matthias Stoll, Klaus Schwarz, Bodo Grimbacher, Reinhold E Schmidt, Faranaz Atschekzei
Here we describe novel mutations in recombination activation gene 1 (RAG1) in a compound heterozygous male patient with combined T and B cell immunodeficiency (CID). Clinical manifestations besides antibody deficiency included airway infections, granulomatosis and autoimmune features. He died at the age of 37 due to PML caused by JC virus infection. By targeted next-generation sequencing we detected post mortem in this patient three mutations in RAG1. One allele harbored two novel mutations (c.1123C>G, p...
February 16, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28232030/phase-i-trial-of-low-dose-interleukin-2-therapy-in-patients-with-wiskott-aldrich-syndrome
#3
Soma Jyonouchi, Brenda Gwafila, Lavesh A Gwalani, Maria Ahmad, Chistopher Moertel, Cecil Holbert, Ji Young Kim, Nathan Kobrinsky, Sumita Roy-Ghanta, Jordan S Orange
BACKGROUND: Low dose IL-2 can restore the function of T and NK cells from Wiskott-Aldrich (WAS) patients.However, the safety of in vivo IL-2 in WAS is unknown. OBJECTIVES: A phase-I study to assess safety of low dose IL-2 in WAS. METHODS: Patients received 5 daily subcutaneous IL-2 injections, every 2months, for three courses.A "3+3" dose escalation method was used. RESULTS: 6 patients received the 0.5millionunits/m(2)/day dose without serious adverse events...
February 13, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28167306/non-receptor-type-proline-rich-protein-tyrosine-kinase-2-pyk2-is-a-possible-therapeutic-target-for-kawasaki-disease
#4
Chinatsu Suzuki, Akihiro Nakamura, Noriko Miura, Kunityoshi Fukai, Naohito Ohno, Tomoyo Yahata, Akiko Okamoto-Hamaoka, Maiko Fujii, Ayako Yoshioka, Yuki Kuchitsu, Kazuyuki Ikeda, Kenji Hamaoka
Kawasaki disease (KD) is a paediatric vasculitis whose pathogenesis remains unclear. Based on experimental studies using a mouse model for KD, we report here that proline-rich protein tyrosine kinase 2 (Pyk2) plays a critical role in the onset of KD-like murine vasculitis. The mouse model for KD was prepared by administrating a Candida albicans water-soluble fraction (CAWS).Unlike CAWS-treated WT mice, CAWS-treated Pyk2-Knockout (Pyk2-KO) mice did not develop apparent vasculitis. A sustained increase in MIG/CXCL9 and IP-10/CXCL10, both of which have potent "angiostatic" activity, was observed in CAWS-treated Pyk2-KO mice...
February 3, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28163195/positive-selection-of-type-ii-collagen-reactive-cd80-high-marginal-zone-b-cells-in-dba-1-mice
#5
Chanho Park, In Seong Kho, Jeong In Yang, Min-Jung Kim, Sunhoo Park, Hoon-Suk Cha, Jaejoon Lee, Tae Jin Kim
To investigate whether dysregulated selection of autoreactive marginal zone (MZ) B cells is involved in autoimmune diseases, we examined MZ B cell profile in multiple strains of mice, and found that type II collagen (CII)-reactive autoreactive CD80(high) MZ B cells spontaneously developed in the DBA/1, but not in C57BL/6 mice. CD80(high) MZ B cells that were characteristically found in DBA/1 mice expressed higher levels of TACI, SLAM3, and SLAM6 than the usual CD80(low) MZ B cells. Notably, the CD80(high) MZ B cells were more sensitive to ibrutinib, a Bruton's tyrosine kinase inhibitor, than CD80(low) MZ or follicular B cells and their transient depletion via intravenous injection of ibrutinib significantly delayed the induction of collagen-induced arthritis (CIA)...
February 2, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28161408/anti-blys-antibody-reduces-the-immune-reaction-against-enzyme-and-enhances-the-efficacy-of-enzyme-replacement-therapy-in-fabry-disease-model-mice
#6
Yohei Sato, Hiroyuki Ida, Toya Ohashi
Formation of antibodies against a therapeutic enzyme is an important complication during enzyme replacement therapy (ERT) for lysosomal storage diseases. Fabry disease (FD) is caused by a deficiency of alpha-galactosidase (GLA), which results in the accumulation of globotriaosylceramide (GL-3). We have shown immune tolerance induction (ITI) during ERT in FD model mice by using an anti-B lymphocyte stimulator (anti-BlyS) antibody (belimumab). A single dose of the anti-BlyS antibody temporarily lowered the percentage of B cells and IgG antibody titer against recombinant human GLA...
February 2, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28161409/gain-of-function-stat1-mutations-are-associated-with-intracranial-aneurysms
#7
Mete Dadak, Roland Jacobs, Jelena Skuljec, Adan Chari Jirmo, Özlem Yildiz, Frank Donnerstag, Niklas Thomas Baerlecken, Reinhold Ernst Schmidt, Heinrich Lanfermann, Thomas Skripuletz, Philipp Schwenkenbecher, Christoph Kleinschnitz, Hayrettin Tumani, Martin Stangel, Refik Pul
Chronic mucocutaneous candidiasis, characterized by persistent or recurrent fungal infections, represents the clinical hallmark in gain-of-function (GOF) signal transducer and activator of transcription 1 (STAT1) mutation carriers. Several cases of intracranial aneurysms have been reported in patients with GOF STAT1 mutation but the paucity of reported cases likely suggested this association still as serendipity. In order to endorse this association, we link the development of intracranial aneurysms with STAT1 GOF mutation by presenting the two different cases of a patient and her mother, and demonstrate upregulated phosphorylated STAT4 and IL-12 receptor β1 upon stimulation in patient's blood cells...
February 1, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28161407/a-novel-mutation-in-tap1-gene-leading-to-mhc-class-i-deficiency-report-of-two-cases-and-review-of-the-literature
#8
Damla Hanalioglu, Deniz Cagdas Ayvaz, Tuba Turul Ozgur, Mirjam van der Burg, Ozden Sanal, Ilhan Tezcan
Major histocompatibility complex (MHC) class I deficiency syndrome is a rare primary immunodeficiency caused by mutations in the peptide transporter complex associated with antigen presentation (TAP) gene which plays a crucial role in intracellular peptide antigen presentation. A few cases have been reported to date. Recurrent sinopulmonary infections and skin ulcers are main characteristics of the syndrome. Here we report two siblings diagnosed with TAP1 deficiency syndrome associated only with recurrent sinopulmonary infections with the description of a novel mutation leading to a premature stop codon in TAP1 gene and review of the relevant literature...
February 1, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28131926/gad-specific-t-cells-are-induced-by-gad-alum-treatment-in-type-1-diabetes-patients
#9
Mikael Pihl, Hugo Barcenilla, Stina Axelsson, Mikael Chéramy, Linda Åkerman, Ingela Johansson, Johnny Ludvigsson, Rosaura Casas
Administration of Glutamic Acid Decarboxylase (GAD)65 formulated in aluminium hydroxide preserved insulin secretion in a phase II trial in recent onset Type 1 Diabetes. A subsequent European phase III trial was closed at 15months after failing to reach primary endpoint, but the majority of the Swedish patients completed the 21months follow-up. We studied the frequencies and phenotype of T cells, suppressive capacity of Tregs, GAD65-induced proliferation, and frequencies of T cells with a GAD65-specific TCR in Swedes participating in the trial...
January 26, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28126470/ataxia-telangiectasia-immunodeficiency-and-survival
#10
Nienke J H van Os, Anne F M Jansen, Marcel van Deuren, Asgeir Haraldsson, Nieke T M van Driel, Amos Etzioni, Michiel van der Flier, Charlotte A Haaxma, Tomohiro Morio, Amit Rawat, Michiel H D Schoenaker, Annarosa Soresina, Alexander M R Taylor, Bart P C van de Warrenburg, Corry M R Weemaes, Nel Roeleveld, Michèl A A P Willemsen
Ataxia-telangiectasia (AT) is a neurodegenerative disorder characterized by ataxia, telangiectasia, and immunodeficiency. An increased risk of malignancies and respiratory diseases dramatically reduce life expectancy. To better counsel families, develop individual follow-up programs, and select patients for therapeutic trials, more knowledge is needed on factors influencing survival. This retrospective cohort study of 61 AT patients shows that classical AT patients had a shorter survival than variant patients (HR 5...
January 23, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28115292/cadherin-11-as-a-therapeutic-target-in-chronic-inflammatory-rheumatic-diseases
#11
REVIEW
Petros P Sfikakis, Nikolaos I Vlachogiannis, Panagiotis F Christopoulos
Cadherin-11 has been identified as a key regulator of synovial architecture mediating contact between Fibroblast-like Synoviocytes and organization in the lining layer. A central role for cadherin-11 has also been suggested in the formation of the rheumatoid pannus. Therapeutic targeting of cadherin-11 results in amelioration of autoimmune experimental arthritis, as well as of experimental fibrosis. In addition, cadherin-11 expression is upregulated in the synovium of patients with chronic inflammatory arthritis, whereas detection of cadherin-11 mRNA transcripts in the peripheral blood has been associated with more severe disease phenotypes in two prototypic conditions of chronic joint inflammation and fibrosis, namely, rheumatoid arthritis and systemic sclerosis, respectively...
January 21, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28108365/neutrophil-subset-responses-in-infants-with-severe-viral-respiratory-infection
#12
Bart Cortjens, Sarah A Ingelse, Job C Calis, Alexander P Vlaar, Leo Koenderman, Reinout A Bem, Job B van Woensel
Neutrophils are the predominant inflammatory cells recruited to the respiratory tract as part of the innate immune response to viral infections. Recent reports indicate the existence of distinct functional neutrophil subsets in the circulatory compartment of adults, following severe inflammatory conditions. Here, we evaluated the occurrence of neutrophil subsets in blood and broncho-alveolar lavage fluid during severe viral respiratory infection in infants based on CD16/CD62L expression. We show that during the course of severe respiratory infection infants may develop four heterogeneous neutrophil subsets in blood (mature, immature, progenitor, and suppressive neutrophils), each with distinct activation states...
January 17, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28108364/from-natalizumab-to-fingolimod-in-eight-weeks-immunological-clinical-and-radiological-data-in-quest-of-the-optimal-switch
#13
Andrea Harrer, Georg Pilz, Katrin Oppermann, Marlene Sageder, Shahrzad Afazel, Elisabeth Haschke-Becher, Theo Rispens, Annick de Vries, Mark McCoy, Vlado Stevanovic, Wolfgang Hitzl, Eugen Trinka, Jörg Kraus, Johann Sellner, Peter Wipfler
Natalizumab (NZB) discontinuation during a treatment change is associated with recurrence of disease activity in a significant proportion of multiple sclerosis (MS) patients. The immunological basis why disease reactivation occurs in selected patients is unresolved. In search of a prognostic biomarker for a safe and effective transition from NZB to fingolimod, we monitored five parameters related to pharmacokinetic and pharmacodynamic effects of the two drugs in 12 MS patients until six months on fingolimod...
January 17, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28104464/genetic-defects-in-pi3k%C3%AE-affect-b-cell-differentiation-and-maturation-leading-to-hypogammaglobulineamia-and-recurrent-infections
#14
Marjolein Wentink, Virgil Dalm, Arjan C Lankester, Pauline A van Schouwenburg, Liesbeth Schölvinck, Tomas Kalina, Radana Zachova, Anna Sediva, Annechien Lambeck, Ingrid Pico-Knijnenburg, Jacques J M van Dongen, Malgorzata Pac, Ewa Bernatowska, Martin van Hagen, Gertjan Driessen, Mirjam van der Burg
BACKGROUND: Mutations in PIK3CD and PIK3R1 cause activated PI3K-δ syndrome (APDS) by dysregulation of the PI3K-AKT pathway. METHODS: We studied precursor and peripheral B-cell differentiation and apoptosis via flowcytometry. Furthermore, we performed AKT-phosphorylation assays and somatic hypermutations (SHM) and class switch recombination (CSR) analysis. RESULTS: We identified 13 patients of whom 3 had new mutations in PIK3CD or PIK3R1. Patients had low total B-cell numbers with increased frequencies of transitional B cells and plasmablasts, while the precursor B-cell compartment in bone marrow was relatively normal...
January 17, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28099879/high-dose-baff-receptor-specific-mab-sirna-conjugate-generates-fas-expressing-b-cells-in-lymph-nodes-and-high-affinity-serum-autoantibody-in-a-myasthenia-mouse-model
#15
Naazneen Ibtehaj, Karl E Anderson, Ruksana Huda
We investigated potential therapeutic effects of a conjugate of BAFF receptor specific- monoclonal antibody and short interference RNA in a mouse model of myasthenia gravis (EAMG). Whereas high-dose siRNA conjugate resulted in significant accumulation of Fas expressing CD19+/ B220+ cells and concurrent expression of type 1 interferon in lymph nodes, low-dose conjugate did not induce FAS expression but caused marked BAFF receptor deficiency in lymph nodes that was further associated with improved MG symptoms...
January 15, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28095319/autophagy-and-autoimmunity
#16
REVIEW
Dennis J Wu, Iannis E Adamopoulos
Autophagy is a highly conserved protein degradation pathway from yeasts to humans that is essential for removing protein aggregates and misfolded proteins in healthy cells. Recently, autophagy-related genes polymorphisms have been implicated in several autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, psoriasis, and multiple sclerosis. Numerous studies reveal autophagy and autophagy-related proteins also participate in immune regulation. Conditional deletions of autophagy-related proteins in mice have rendered protection from experimental autoimmune encephalomyelitis, and TNF-mediated joint destruction in animal models of multiple sclerosis and experimental arthritis respectively...
January 15, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28093362/hypoxia-inducible-factor-1%C3%AE-inhibition-modulates-airway-hyperresponsiveness-and-nitric-oxide-levels-in-a-balb-c-mouse-model-of-asthma
#17
Carola Dewitz, Elisa McEachern, Stephanie Shin, Kathryn Akong, Dale G Nagle, David H Broide, Praveen Akuthota, Laura E Crotty Alexander
: Hypoxia-inducible factor (HIF)-1α is a master regulator of inflammation and is upregulated in alveolar macrophages and lung parenchyma in asthma. HIF-1α regulates select pathways in allergic inflammation, and thus may drive particular asthma phenotypes. This work examines the role of pharmacologic HIF-1α inhibition in allergic inflammatory airway disease (AIAD) pathogenesis in BALB/c mice, which develop an airway hyperresponsiveness (AHR) asthma phenotype. Systemic treatment with HIF-1α antagonist YC-1 suppressed the increase in HIF-1α expression seen in control AIAD mice...
January 14, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28093361/neil1-is-a-candidate-gene-associated-with-common-variable-immunodeficiency-in-a-patient-with-a-chromosome-15q24-deletion
#18
Rosa Romano, Apostolos Zaravinos, Kyriaki Liadaki, Rozina Caridha, Johanna Lundin, Göran Carlsson, Jacek Winiarski, Qiang Pan-Hammarström, Lennart Hammarström
We report the first patient with an interstitial deletion of chromosome 15q24.1-q24.3 associated with common variable immunodeficiency (CVID). The 18-year old female patient's clinical and immunological phenotype was compared with 8 additional previously published patients with chr15q24 deletions. A CGH analysis estimated the deletion to be 3.767Mb in size (chr15: 74,410,916-78,178,418) and the result was confirmed using qRT-PCR. We defined an immune-related commonly deleted region (ICDR) within the chromosomal band 15q24...
January 14, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28089609/de-immunized-and-functional-therapeutic-deft-versions-of-a-long-lasting-recombinant-alpha-interferon-for-antiviral-therapy
#19
Eduardo F Mufarrege, Sofía Giorgetti, Marina Etcheverrigaray, Frances Terry, William Martin, Anne S De Groot
Interferon α (IFN-α) exerts potent antiviral, immunomodulatory, and antiproliferative activity and have proven clinical utility in chronic hepatitis B and C virus infections. However, repeated IFN-α administration induces neutralizing antibodies (NAb) against the therapeutic in a significant number of patients. Associations between IFN-α immunogenicity and loss of efficacy have been described. So as to improve the in vivo biological efficacy of IFN-α, a long lasting hyperglycosylated protein (4N-IFN) derived from IFN-α2b wild type (WT-IFN) was developed...
January 10, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/28063939/superoxide-dismutase-3-attenuates-experimental-th2-driven-allergic-conjunctivitis
#20
Hyun Jung Lee, Bo-Mi Kim, Soojung Shin, Tae-Yoon Kim, So-Hyang Chung
Allergic conjunctivitis is an inflammatory eye disease mediated by Th2 type immune response. The role of extracellular superoxide dismutase 3 (SOD3) in immune response and allergic conjunctival inflammation was examined in a murine model for experimental allergic conjunctivitis (EAC). Allergic conjunctivitis was induced in mice by allergen challenge with ovalbumin in alum via the conjunctival sac. SOD3 was topically applied and allergy indicators were compared. Clinical signs associated with conjunctivitis, such as OVA-specific IgE production, IgG1/G2a ratio and eosinophil infiltration, were drastically reduced in mice treated with SOD3...
January 4, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
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