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  • Identification of a novel de novo gain-of-function mutation of PIK3CD in a patient with activated phosphoinositide 3-kinase δ syndrome
    Clin. Immunol. (IF 3.557) Pub Date : 2018-08-20
    Ying Luo, Yu Xia, Wenjing Wang, Zhichuan Li, Yan Jin, Yifeng Gong, Tingyan He, Qiu Li, Chengrong Li, Jun Yang

    Activated phosphoinositide 3-kinase δ (PI3Kδ) syndrome is a newly defined and relatively common primary immunodeficiency, which is caused by heterozygous gain-of-function (GOF) mutations in PIK3CD or PIK3R1. Here, we report a novel de novo GOF mutation (c.1570 T > A, p.Y524N) in PIK3CD in a 6-year-old Chinese girl. The patient suffered recurrent sinopulmonary infection, bronchiectasis, lymphoproliferation, herpesvirus infection, and distinctive nodular lymphoid hyperplasia of mucosal surfaces. Immunological analysis revealed increased CD4+ T cell senescence and B cell immaturity. Further analysis revealed an increase in almost all CD4+ T cell subsets to varying degrees, including effector T cells and Treg cells. Increased levels of plasma T cell-related cytokines corroborated these results. Hyperactivation of the PI3Kδ-Akt-mTOR signaling pathway was also confirmed. Treatment with rapamycin ameliorated the lymphoproliferative immunodeficiency caused by hyperactivation of mTOR. These results expand genetic spectrum of APDS and will facilitate further study of the genotype-phenotype correlation in those with PIK3CD mutations.

  • Efficacy of anti-TNF alpha in severe and refractory major vessel involvement of Behcet's disease: A multicenter observational study of 18 patients
    Clin. Immunol. (IF 3.557) Pub Date : 2018-08-18
    A.C. Desbois, L. Biard, O. Addimanda, M. Lambert, E. Hachulla, D. Launay, F. Ackerman, L. Pérard, A. Hot, F. Maurier, C. Mausservey, F. Bernard, N. Noel, L. Alric, T. Mirault, F. Cohen, S. Boussouar, M. Resche-Rigon, D. Saadoun

    Objective To describe the outcome and tolerance in patients treated with anti-TNFα in severe and refractory major vessel disease in Behçet's disease (BD). Methods A multicenter study evaluating 18 refractory BD patients with major vessel involvement [pulmonary artery (n = 4), aorta (n = 4) or peripheral artery aneurysm (n = 1) and/or pulmonary artery (n = 7), inferior vena cava (n = 5), or intra-cardiac (n = 3) thrombosis or Budd Chiari Syndrome (n = 2)] treated with anti-TNFα agents. Results Vascular remission was achieved in 16 (89%) patients. The 9 months risk of relapse was significantly higher with conventional immunosuppressants used prior anti-TNFα agents as compared to anti-TNFα therapy [OR = 8.7 (1.42–62.6), p = 0.03]. The median daily dose of corticosteroids significantly decreased at 12 months. Side effects included infection (n = 4) and pulmonary edema (n = 1). Conclusion TNFα-antagonists are safe and might be associated with a decreased risk of relapse at 9 months compared to conventional immunosuppressants in BD patients with major vessels disease.

  • Induction of plasmablasts by follicular helper T cell-CXCL13 axis upon occurrence of herpes zoster
    Clin. Immunol. (IF 3.557) Pub Date : 2018-08-16
    Kensuke Fukuchi, Takatoshi Shimauchi, Kazuki Tatsuno, Yoshiki Tokura

    Herpes zoster (HZ) is a recurrent varicella zoster virus (VZV) infection. Follicular helper T (Tfh) cells produce IL-21 and CXCL13, which contributes to the differentiation of plasmablasts. Plasmablasts are involved in the VZV-specific antibody production. We investigated the kinetics of circulating plasmablasts and circulating Tfh (cTfh) cells in 43 HZ patients. Plasma IL-21 and CXCL13 levels were also measured. We found an increase of circulating plasmablasts during the clinical course of HZ. The frequency of circulating plasmablasts positively correlated with VZV-specific IgG titers, frequency of activated cTfh cells, and plasma CXCL13 levels, but did not correlate with plasma IL-21 levels. In a representative case, the kinetics peaked in the order of cTfh cells, CXCL13, plasmablasts, and VZV IgG titer. These results suggest that cTfh-CXCL13 may have a crucial role in the differentiation of B cells into VZV-specific IgG-producing plasmablasts, resulting in boosting immunity against VZV reactivation.

  • Th1/17 cells, a subset of Th17 cells, are expanded in patients with active systemic lupus erythematosus
    Clin. Immunol. (IF 3.557) Pub Date : 2018-08-16
    Anastasia Tsanaktsi, Elena E. Solomou, Stamatis-Nick C. Liossis

    Skewed cytokine production characterizes T cells in Systemic Lupus Erythematosus (SLE). Among Th17 cells that are expanded in lupus, a subset (Th1/17) retains the ability to produce IFNγ.We aimed to analyze Th17 and Th1/17 cells in patients with SLE. Patients with active disease displayed increased percentages of circulating Τh17 and Th1/17 cells. Stimulated T cells from patients with lupus secreted significantly more IL-17 compared to healthy donors.Also, T cells from patients with active SLE released significantly lower levels of IFN-γ compared to controls. However, following stimulation, levels of IFN-γ also rose significantly. Our data suggest that lupus Th1/17 cells are not only expanded but also functional.In summary, in this study it was shown that patients with active SLE display increased Th17 and functional Th1/17 cells. This impaired T-cell axis might represent a possible future therapeutic target.

  • Two siblings with PRKDC defect who presented with cutaneous granulomas and review of the literature
    Clin. Immunol. (IF 3.557) Pub Date : 2018-08-16
    Saliha Esenboga, Can Akal, Betül Karaatmaca, Baran Erman, Sibel Dogan, Diclehan Orhan, Kaan Boztug, Deniz Ayvaz, İlhan Tezcan

    V(D)J recombination, during which recognition and repair of broken DNA chains are accomplished by non-homologous end joining pathway, is a critical process in B and T cell development.Null mutations of each enzyme or protein of this pathway result in T- B- NK+ severe combined immunodeficiency whereas hypomorphic mutations result in atypical(leaky)severe combined immunodeficiency forms. We present two siblings with PRKDC (Protein Kinase, DNA-Activated, Catalytic Polypeptide) mutation who presented with granulomatous skin lesions and recurrent lung infections. Primary immune deficiencies may initially present with skin findings. Disruption in central and peripheral B-cell tolerance and impaired intrathymic T-cell maturation,a central player in T-cell tolerance, have been identified as the mechanism of autoimmunity and granuloma seen in patients. The variation in clinical phenotypes of patients with PRKDC mutation suggests that additional factors such as modifying genes, epigenetic and environmental factors may affect the severity and clinical phenotype of the disease. Functional studies during the follow-up and evaluation before and after hematopoeitic stem cell transplantation will hopefully increase our knowledge about the autoimmune and inflammatory process of the disease spectrum.

  • MyD88 signaling in T regulatory cells by endogenous ligands dampens skin inflammation in filaggrin deficient mice
    Clin. Immunol. (IF 3.557) Pub Date : 2018-08-09
    Sabine Hoff, Michiko K. Oyoshi, Jason L. Hornick, Raif S. Geha,

    Mutations in filaggrin are associated with atopic dermatitis. Filaggrin-deficient flaky tail (Flgft/ft) mice develop spontaneous inflammatory skin lesion that wax and wane. We show that loss of MyD88 promotes the persistence of skin lesions in Flgft/ft mice and exaggerates their expression of the Th17-associated cytokines Il7a and Il22. The development and persistence of skin lesions in Flgft/ft mice was independent of the microbiota. MyD88-mediated signals are shown to be important for the accumulation of T regulatory cells (Tregs) in lesional skin of Flgft/ft mice. Adoptive transfer of WT Tregs dampened the severity of skin lesions in MyD88−/−/Flgft/ft mice. These results suggest that MyD88 signaling in Treg cells by endogenous ligands attenuates skin inflammation in filaggrin deficiency.

  • Formononetin attenuated allergic diseases through inhibition of epithelial-derived cytokines by regulating E-cadherin
    Clin. Immunol. (IF 3.557) Pub Date : 2018-08-02
    Li Lianqu, Wang Yan, Wang Xiaoyu, Tao Yu, Bao Kaifa, Hua Yongqing, Jiang Guorong, Hong Min

    Radix Astragali, has long been used to alleviate allergic diseases (ADs). Formononetin is one of the major active components in Radix Astragali, but its mechanism on ADs is not definitively known. The fluorescein isothiocyanate isomer-induced atopic contact dermatitis mouse model and poly I:C or lipopolysaccharide-treated HaCaT cells were used to examine thymic stromal lymphopoietin (TSLP)/interleukin (IL)-33 production and expression of E-cadherin. After administration of formononetin, TSLP/IL-33 levels decreased both in vitro and in vivo, while E-cadherin was increased in vivo and restored in vitro. Furthermore, small interference RNA silencing of E-cadherin resulted in elevated levels of TSLP, whereas the inhibitory effect of formononetin on TSLP was no longer observed. In addition, TSLP resulted in no detectable changes in delocalization or protein expression of E-cadherin in HaCaT cells. These results indicated that formononetin showed a protective effect in ADs, which was correlated with decreasing TSLP/IL-33 production via regulation of E-cadherin.

  • Epitope mapping of anti-ALK antibodies in children with anaplastic large cell lymphoma
    Clin. Immunol. (IF 3.557) Pub Date : 2018-08-01
    Fabian Knörr, Simone Weber, Vijay K. Singh, Karen Pulford, Alfred Reiter, Wilhelm Woessmann, Christine Damm-Welk

    Patients with Nucleophosmin (NPM)-Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) mount ALK autoantibodies. The titer of these autoantibodies inversely correlates with the risk of relapse.The epitopes recognized by these autoantibodies in NPM-ALK might be associated with different ALK-antibody levels. We used overlapping peptide microarray technology to analyze epitope-binding to NPM-ALK by plasma or serum from 129 ALK-positive ALCL patients and 21 controls. Antibodies present in sera from ALCL patients bound to epitopes mainly in the C-terminal region of the ALK portion of NPM-ALK (amino acid positions 469–496, 561–588, 617–644). Patients with higher ALK antibody titers detected the epitope 561–588 more frequently as well as three further epitopes at the N-terminus of the kinase domain compared to patients with intermediate and low titers.These results identify new potential target epitopes for immunotherapy in ALK-positive ALCL. The methodology can be adapted for more reproducible analyses of tumor antigen detection.

  • Deficiencies in the CD19 complex
    Clin. Immunol. (IF 3.557) Pub Date : 2018-07-31
    Marjolein W.J. Wentink, Menno van Zelm, Jacques J.M. van Dongen, Klaus Warnatz, Mirjam van der Burg

    Signaling via the CD19-complex, consisting of CD19, CD81, CD21 and CD225, is critically important for B-cell development, differentiation and maturation. In this complex, each protein has its own distinct function. Over the past decade, 15 patients with antibody deficiency due to deficiencies in the CD19-complex have been described. These patients have deficiencies in different complex-members, all caused by either homozygous or compound heterozygous mutations. Although all patients had antibody deficiencies, the clinical phenotype was different per deficient protein. We aimed to provide an overview of what is known about the function of the different complex-members, knowledge from mouse-studies and to summarize the clinical phenotypes of the patients. Combining this knowledge together can explain why deficiencies in different members of the same complex, result in disease phenotypes that are alike, but not the same.

  • Autosomal Recessive Agammaglobulinemia - first case with a novel TCF3 mutation from Pakistan
    Clin. Immunol. (IF 3.557) Pub Date : 2018-07-29
    Sonia Qureshi, Muhammad Dawood Amir Sheikh, Farah Naz Qamar, Wayne Bainter, Janet Chou, Raif S. Geha

    Autosomal Recessive Agammaglobulinemia (ARA) is an uncommon type of primary immunodeficiency characterized by mutations in genes responsible for early B cell differentiation and function. One such gene is the TCF3 gene, which encodes a transcription factor important for immunoglobulin gene expression. We present the case of a 9 year old girl with history of diarrhea and recurrent pneumonias. Laboratory investigation showed significantly reduced levels of immunoglobulins along with a significant fall in the number of CD19+ cells. Genetic analysis identified a TCF3 gene base deletion covering exons 5–11.

  • Th1-skewed profile and excessive production of proinflammatory cytokines in a NFKB1-deficient patient with CVID and severe gastrointestinal manifestations
    Clin. Immunol. (IF 3.557) Pub Date : 2018-07-29
    Romina Dieli-Crimi, Mónica Martínez-Gallo, Clara Franco-Jarava, Maria Antolin, Laura Blasco, Ida Paramonov, Maria E. Semidey, Antoni Álvarez Fernández, Xavier Molero, Julio Velásquez, Andrea Martín-Nalda, Ricardo Pujol-Borrell, Roger Colobran

    Monoallelic loss-of-function mutations in NFKB1 were recently recognized as the most common monogenic cause of common variable immunodeficiency (CVID). The prototypic clinical phenotype of NFKB1-deficient patients includes common CVID features, such as hypogammaglobulinaemia and sinopulmonary infections, plus other highly variable individual manifestations. Here, we describe a patient with a profound CVID phenotype and severe gastrointestinal manifestations, including chronic and recurrent diarrhoea. Using an NGS customized panel of 323 genes related to primary immunodeficiencies, we identified a novel monoallelic loss-of-function mutation in NFKB1 leading to a truncated protein (c.1149delT/p.Gly384Glu ∗ 48). Interestingly, we also found a rare variant in NOD2 previously associated with Crohn's disease (p.His352Arg). Our patient had hypogammaglobulinaemia with a small number of B cells, most of which were naïve. The most noteworthy findings included marked skewing towards a Th1 phenotype in peripheral blood T cells and excessive production of proinflammatory cytokines (IL-1β, TNFα). The patient's 6-year-old daughter, a carrier of the NFKB1 mutation, is clinically asymptomatic, but has started to show cellular and molecular changes. This case of NFKB1 deficiency appears to be a combination of immunodeficiency and a hyperinflammatory state. The current situation of the patient's daughter provides a glimpse of the preclinical phase of the condition.

  • Toll-like receptor 9 ligands increase type I interferon induced B-cell activating factor expression in chronic rhinosinusitis with nasal polyposis
    Clin. Immunol. (IF 3.557) Pub Date : 2018-07-26
    Jun Xu, Jin-Woo Lee, Soo-Kyoung Park, Sung-Bok Lee, Young-Hoon Yoon, Sun-Hee Yeon, Ki-Sang Rha, Ji-Ae Choi, Chang-Hwa Song, Yong Min Kim

    B-cell activating factor (BAFF) has been proposed to play a crucial role in the pathogenesis of chronic rhinosinusitis with nasal polyp (CRSwNP). The aim of this study was to evaluate the role of toll-like receptor (TLR) 9-mediated BAFF activation on the pathogenesis of CRSwNP. NP and uncinate tissue (UT) were obtained from patients with CRSwNP or CRS without NP, and control subjects. The expression of TLR9, high mobility group box-1 protein (HMGB1), type I interferon (IFN), BAFF, and anti-double stranded DNA (dsDNA) antibody were examined in the tissues and the cultured dispersed NP cells (DNPCs). The expression of TLR9, HMGB1, type I IFN, BAFF, and anti-dsDNA antibody were elevated in NP tissue compared to the UTs. Exposure to TLR9 agonist increased the type I IFN expression in vitro, which further increased BAFF production. In conclusion, we provided a novel therapeutic potential of TLR9 agonist in CRSwNP.

  • Clinical and molecular features of X-linked hyper IgM syndrome – An experience from North India
    Clin. Immunol. (IF 3.557) Pub Date : 2018-07-25
    Amit Rawat, Babu Mathew, Vignesh Pandiarajan, Ankur Jindal, Madhubala Sharma, Deepti Suri, Anju Gupta, Shubham Goel, Adil Karim, Biman Saikia, Ranjana W. Minz, Kohsuke Imai, Shigeaki Nonoyama, Osamu Ohara, Silvia Clara Giliani, Luigi D. Notarangelo, Koon-Wing Chan, Yu-Lung Lau, Surjit Singh

    X-linked hyper IgM Syndrome (XLHIGM), the most frequent form of the Hyper IgM syndromes is a primary immune deficiency resulting from a mutation in the CD40 ligand gene (CD40LG). We analyzed the clinical and laboratory features of ten patients with XLHIGM, who were diagnosed at a tertiary care hospital in North India. Most common infections were sinopulmonary infections (80%) and diarrhea (50%). Sclerosing cholangitis and necrotising fasciitis were noted in one patient each. Three novel mutations in CD40LG (c.429_429 delA, p. G144DfsX5; c.500 G > A, p.G167E and c.156 G > C, p.K52 N) were detected. In addition, we found one missense mutation, two splice site mutations and two large deletions, which have been previously reported. Four (4) patients had expired at the time of analysis. We report the first series of XLHIGM from North India where we have documented unique features such as pulmonary alveolar proteinosis and infections with Mycobacterium sp.

  • High frequencies of asymptomatic Epstein-Barr virus viremia in affected and unaffected individuals with CTLA4 mutations
    Clin. Immunol. (IF 3.557) Pub Date : 2018-07-24
    Akihiro Hoshino, Kay Tanita, Kenji Kanda, Ken-Ichi Imadome, Yoshiaki Shikama, Takahiro Yasumi, Kohsuke Imai, Masatoshi Takagi, Tomohiro Morio, Hirokazu Kanegane

    Patients with CTLA4 mutations present with autoimmune diseases, lymphoproliferation, and hypogammaglobulinemia, and a subset of patients developed Epstein-Barr virus (EBV)-associated malignancies, suggesting an impaired immune function against EBV. Here we investigated EBV infection in individuals with CTLA4 mutations. We measured EBV viral DNA in healthy individuals, individuals with autoimmune diseases, and individuals with CTLA4 mutations. In addition, we evaluated the numbers and function of EBV-specific T cells, invariant NKT cells, and NK cells. More than half of individuals with CTLA4 mutations including asymptomatic ones had detectable EBV DNA, which is a significantly higher frequency with higher viral loads compared with healthy and disease controls. However, individuals with CTLA4 mutations had almost normal immunity against EBV. Individuals with CTLA4 mutations have an increased susceptibility to Epstein-Barr virus infections. Asymptomatic viremia occurs at high frequencies, which can be persistent and can occur in unaffected individuals.

  • Diagnosis of DOCK8 deficiency using Flow cytometry Biomarkers: an Egyptian Center experience
    Clin. Immunol. (IF 3.557) Pub Date : 2018-07-24
    Safa S. Meshaal, Rabab E. El Hawary, Alia Eldash, Bodo Grimbacher, Nadezhda Camacho-Ordonez, Dalia S. Abd Elaziz, Nermeen M. Galal, Jeannette A. Boutros, Shereen M. Shawky, Aisha M. Elmarsafy

    In the past few years, several genes were shown to be implicated in various forms of the Hyper Immunoglobulin E syndrome. The present study is the first to describe a cohort of DOCK8 deficiency patients from Egypt. The study included 15 patients with features of combined immunodeficiency (CID) suggestive of DOCK8 deficiency. Flow cytometry was used for evaluation of DOCK8 expression and studying different immunological characteristics of those patients including evaluation of Th17, Tregs, T and B lymphocytes differentiation and the effect of the DOCK8 deficiency on the activation of the STAT3. Diagnosis was confirmed by mutational analysis. Profound defects in Th17 cells and Tregs were observed in all patients with impaired STAT3 phosphorylation, indicating that DOCK8 plays a pivotal role in the STAT3 signaling pathway. These findings together with decrease in memory B cells and defective DOCK8 expression by flow cytometry can confirm the diagnosis.

  • CD4 T cell loss and Th2 and Th17 bias are associated with the severity of severe fever with thrombocytopenia syndrome (SFTS)
    Clin. Immunol. (IF 3.557) Pub Date : 2018-07-20
    Meng-Meng Li, Wen-Jing Zhang, Xiu-Fang Weng, Ming-Yue Li, Jia Liu, Yan Xiong, Shu-E Xiong, Cong-Cong Zou, Hua Wang, Meng-ji Lu, Dong-Liang Yang, Cheng Peng, Xin Zheng

    Severe fever with thrombocytopenia syndrome (SFTS) is a newly emerging infectious disease caused by a novel bunyavirus with high mortality. Immune suppression is thought to be crucial in disease progression. However, data on immune responses during SFTS are scarce. This study aimed to evaluate the changes in CD4 T-cell subsets throughout the entirety of infection and analyse their relationships with disease severity in SFTS patients. In parallel with CD4 T-cell depletion, decreased Th1, Th2 and Treg numbers, but comparable Th17-cell numbers, were observed in deceased patients compared with those in surviving patients. Additionally, increased Th2 and Th17-cell percentages in the residual CD4 T-cell population led to aberrant Th2/Th1 and Th17/Treg ratios, which were positively correlated with disease severity. Collectively, our data indicated that CD4 T-cell deficiency, Th2 and Th17 bias were closely correlated with the severity of SFTS, indicating therapeutic potential of early immune interventions to ameliorate disease severity.

  • Anti-polysaccharide and anti-diphtheria protective antibodies after 13-valent pneumococcal conjugate vaccination in rheumatoid arthritis patients under immunosuppressive therapy
    Clin. Immunol. (IF 3.557) Pub Date : 2018-07-21
    Sara Caporuscio, Roberto Ieraci, Guido Valesini, Raffaela Teloni, Sabrina Mariotti, Francesca Romana Spinelli, Claudia Ferlito, Simonetta Salemi, Andrea Picchianti Diamanti, Giorgia Meneguzzi, Milica Markovic, Mayla Sgrulletti, Christina von Hunolstein, Luisa Ralli, Antonietta Pinto, Gerardo Salerno, Marco Canzoni, Maria Laura Sorgi, Raffaele D'Amelio

    Immunogenicity of 13-valent pneumococcal polysaccharide (PnPS) conjugate vaccine (PCV13) was evaluated in 38 rheumatoid arthritis patients under immunosuppressive treatment and 20 healthy controls (HC). Antibodies to all PnPS and diphtheria-toxin analogue conjugate protein were measured pre- (T0), 1 (T1), 6 (T2), 12 (T3) months post-immunization. Patients and HC had similar response to individual PnPS. Mean antibody levels to all PnPS but one doubled at T1 compared with T0, with T3 persistence for only 8-7/13 PnPS. Baseline antibody levels was inversely associated with the rate of responders at T1 (T1/T0≥2) to 11/13 PnPS. Few subjects reached protective IgG levels against some serotypes frequently isolated in Italian patients with invasive pneumococcal disease. Antibody response was not influenced by therapy, except the one to PS7F, which was reduced by tumor necrosis factor-α-inhibitors. Vaccination increased also anti-diphtheria IgG. Despite this study substantially confirmed the PCV13 immunogenicity in immunocompromised patients, it also revealed some limitations.

  • Systemic lupus erythematosus-myasthenia gravis overlap syndrome: Presentation and treatment depend on prior thymectomy
    Clin. Immunol. (IF 3.557) Pub Date : 2018-07-17
    Scott Brian Minchenberg, Geeta Chaparala, Zachary Oaks, Katalin Banki, Andras Perl

    In this study, we investigated four patients who met the diagnostic criteria for overlapping systemic lupus erythematosus (SLE) and myasthenia gravis (MG) but responded differently to treatment. All patients were acetylcholine receptor (AChR) and antinuclear antibody positive at the time of SLE diagnosis. Two patients presented with SLE who have been effectively treated with cholinesterase inhibitors for MG. These patients developed SLE with photosensitivity, rash, and arthritis post thymectomy, which had been performed 29 years and 40 years earlier, respectively. Two other patients were found to have AChR antibodies and MG in the context on new-onset SLE. These subjects were responsive to hydroxychloroquine and immunosuppression but failed cholinesterase inhibitors. The evolution of these cases is relevant for the role of thymus in lupus pathogenesis during aging and for treatment selection in SLE-MG overlap patients.

  • Effects of HLA status and HER2 status on outcomes in breast cancer patients at risk for recurrence – Implications for vaccine trial design
    Clin. Immunol. (IF 3.557) Pub Date : 2018-07-17
    O. Jackson Doreen, Trappey A. Francois, Clifton G. Travis, J. Vreeland Timothy, M. Peace Kaitlin, F. Hale Diane, K. Litton Jennifer, L. Murray James, A. Perez Sonia, Papamichail Michael, A. Mittendorf Elizabeth, E. Peoples George

    Immunotherapy, using peptide-based cancer vaccines is being studied to assess its potential in breast cancer. Trials of HLA-restricted peptide vaccines have been difficult to enroll given HLA subtype restrictions. It is necessary to determine the prognostic significance of HLA-status in breast cancer if patients who are ineligible to receive a vaccine due to their HLA-status are used as controls. The impact of targeted tumor associated antigen expression, when it effects eligibility is also important. We examined control patients from two randomized phase II trials that tested HER2-peptide vaccines to determine the effect of HLA-A2 status and HER2 expression on disease-free survival. The analysis showed that HLA-A2-status does not affect disease-free survival, regardless of HER2 expression suggesting that HLA-A2 negative patients can be used as control patients. Additionally, HER2 over-expression was associated with a better disease-free survival in this population, underscoring the need for additional therapies in HER2 low-expressing breast cancer. ClinicalTrials.gov Identifier: NCT00524277

  • Epigenetic alterations in primary Sjögren's syndrome – an overview
    Clin. Immunol. (IF 3.557) Pub Date : 2018-04-09
    Juliana Imgenberg-Kreuz, Johanna K. Sandling, Gunnel Nordmark

    Primary Sjögren's syndrome (pSS) is a chronic autoimmune rheumatic disease characterized by inflammation of exocrine glands, mainly salivary and lacrimal glands. In addition, pSS may affect multiple other organs resulting in systemic manifestations. Although the precise etiology of pSS remains elusive, pSS is considered to be a multi-factorial disease, where underlying genetic predisposition, environmental factors and epigenetic mechanisms contribute to disease development. Epigenetic mechanisms, such as DNA methylation, histone modifications and non-coding RNAs, may constitute a dynamic link between genome, environment and phenotypic manifestation by their modulating effects on gene expression. A growing body of studies reporting altered epigenetic landscapes in pSS suggests that epigenetic mechanisms play a role in the pathogenesis of pSS, and the reversible nature of epigenetic modifications suggests therapeutic strategies targeting epigenetic dysregulation in pSS. This article reviews our current understanding of epigenetic mechanisms in pSS and discusses implications for novel diagnostic and therapeutic approaches.

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

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

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

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

  • HLA-G protein expression in colorectal cancer evaluated by immunohistochemistry and western blot analysis: Its expression characteristics remain enigmatic
    Clin. Immunol. (IF 3.557) Pub Date : 2018-07-10
    Marloes Swets, Anne Wouters, Daniëlle Krijgsman, Ronald L.P. van Vlierberghe, Arnoud Boot, Jaap D. van Eendenburg, Tom van Wezel, Hans Gelderblom, Cornelis J.H. van de Velde, Peter J. van den Elsen, Peter J.K. Kuppen

    HLA-G protein expression could play a role in evasion of tumor immune surveillance. Accumulating evidence demonstrates that HLA-G is expressed in different types of malignancies, including colorectal cancer (CRC). The purpose of the current study was to further unravel whether HLA-G protein expression could play a role in immune evasion of CRC. Therefore, to firmly establish HLA-G protein expression, eight early passage human CRC cell lines and five human rectal cancer tissues were analyzed by western blot analysis. The results obtained by western blot analysis were compared with immunohistochemistry on tumor tissue sections of the same patient. Furthermore, multiple monoclonal antibodies (mAbs), 4H84, MEM-G/1 and 5A6G7, targeting HLA-G were used to unravel staining patterns. We showed that results obtained with immunohistochemistry did not correlate with protein expression detected by western blot analysis, using three different HLA-G targeting mAbs. Furthermore, with respect to the specificity of the mAbs employed, additional immune reactivity was detected using the mAbs MEM-G/1 and 5A6G7 in western blot analysis with K562 control cell lines overexpressing HLA-A2 or HLA-G, all tumor tissues and in two out of eight CRC cell lines. Based on the current study and our previously reported results, we conclude that claiming HLA-G plays a role in immune modulation of CRC seems premature, as results from anti-body based detection of HLA-G protein remain inconclusive. Until the time that detection of HLA-G is sensitive enough to detect all aspects of HLA-G expression in biological samples, rather than transfected cells or long time cultured cell lines, conclusions should be drawn with great care.

  • Hydroxychloroquine as a novel therapeutic approach in mast cell activation diseases
    Clin. Immunol. (IF 3.557) Pub Date : 2018-07-10
    Eric Espinosa, Salvatore Valitutti, Michel Laroche, Camille Laurent, Pol André Apoil, Olivier Hermine, Michel Lavit, Carle Paul, Cristina Bulai Livideanu

    There is no therapeutic agent approved in cutaneous mastocytosis and mast cell activation syndrome. We report the efficacy of hydroxychloroquine in four patients with cutaneous mastocytosis (n = 2) and mast cell activation syndrome (n = 2). We show that this molecule reduces the long-term survival of primary human mast cells, interferes with lysosome function and leads to the accumulation of non-functional tryptase in the mast cell granules. Furthermore, hydroxychloroquine decreases the production of pro-inflammatory mediators.

  • Thrombotic risk assessment and analytical performance of the chemiluminescent analyzer IDS-Isys for the detection of anti-cardiolipin and anti-beta 2 glycoprotein I autoantibodies
    Clin. Immunol. (IF 3.557) Pub Date : 2018-07-11
    Nafai Salma, Lemerle Julie, Bendaoud Boutahar, Le Nuz Sylvie, Eléonore Bettacchioli, Le Ny Fabien, Elisabeth Pasquier, Jousse-Joulin Sandrine, Francis Couturaud, Hillion Sophie, Renaudineau Yves

    Patients with antiphospholipid antibodies (APLA) are predisposed to develop thrombosis, however the standardization of anti-cardiolipin (aCL) and anti-beta 2 glycoprotein I (β2-GPI) Ab assays are challenging. Therefore we decided to test the performance of a new chemiluminescent assay (CLIA), and assayed aCL and aβ2-GPI IgG/M in serum from 120 healthy individuals, 108 patients with idiopathic venous thrombosis, 78 patients with antiphospholipid syndrome (APS), and 64 non-thrombotic APLA-carriers using CLIA IDS-Isys. Very good (aCL/aβ2-GPI IgG) to moderate (aCL/aβ2-GPI IgM) agreement with a commercial and an in house ELISA assay were observed and, in particular, CLIA demonstrated the highest sensitivity in aβ2-GPI IgG detection. Finally, aCL/aβ2-GPI Ab capacity to predict the thrombotic risk was tested showing for CLIA a significant odds ratio (OR) when considering double positivity for aCL/aβ2-GPI IgG, aCL IgG at high levels, and aβ2-GPI IgG at high levels. In conclusion, CLIA improves aβ2-GPI IgG detection and thrombotic risk assessment.

  • Novel minor HLA DR associated antigens in type 1 diabetes
    Clin. Immunol. (IF 3.557) Pub Date : 2018-07-07
    Denise Müller, Tanja Telieps, Anne Eugster, Christina Weinzierl, Manja Jolink, Anette-Gabriele Ziegler, Ezio Bonifacio

    Type 1 diabetes is an autoimmune disease leading to insulin deficiency. Autoantibodies to beta cell proteins are already present in the asymptomatic phase of type 1 diabetes. Recent findings have suggested a number of additional minor autoantigens in patients with type 1 diabetes. We have established luciferase immunoprecipitation systems (LIPS) for anti-MTIF3, anti-PPIL2, anti-NUP50 and anti-MLH1 and analyzed samples from 500 patients with type 1 diabetes at onset of clinical disease and 200 healthy individuals who had a family history of type 1 diabetes but no evidence of beta cell autoantibodies. We show significantly higher frequencies of anti-MTIF3, anti-PPIL2 and anti-MLH1 in recent onset type 1 diabetes patients in comparison to controls. In addition, antibodies to NUP50 were associated with HLA-DRB1*03 and antibodies to MLH1 were associated with HLA-DRB1*04 genotypes.

  • Hydroxychloroquine efficiently suppresses inflammatory responses of human class-switched memory B cells via Toll-like receptor 9 inhibition
    Clin. Immunol. (IF 3.557) Pub Date : 2018-07-04
    Masataka Torigoe, Kei Sakata, Akina Ishii, Shigeru Iwata, Shingo Nakayamada, Yoshiya Tanaka

    Hydroxychloroquine is widely used for autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Although B cells contribute to the pathogenesis of these diseases, the action of hydroxychloroquine on B cells remains unclear. Here we examined the effects of hydroxychloroquine on functions of B cell subsets. Hydroxychloroquine efficiently inhibited the mammalian target of rapamycin complex 1, differentiation of CD19+IgD−CD27+ class-switched memory B cells to plasmablasts and their IgG production, under stimulation with CpG, a Toll-like receptor (TLR)-9 ligand. Hydroxychloroquine also inhibited CpG-induced production of interleukin-6 and tumor necrosis factor-α in B cell subsets. Taken together, hydroxychloroquine markedly suppresses the TLR9-mediated human B cell functions during inflammatory processes. Based on our results, we believe that hydroxychloroquine can be beneficial in the treatment of B cell-mediated autoimmune diseases.

  • APECED in Turkey: A case report and insights on genetic and phenotypic variability
    Clin. Immunol. (IF 3.557) Pub Date : 2018-07-03
    Alessandra Fierabracci, Marsha Pellegrino, Federica Frasca, Sara Sebnem Kilic, Corrado Betterle

    APECED is a rare monogenic recessive disorder caused by mutations in the AIRE gene. In this manuscript, we report a male Turkish patient with APECED syndrome who presented with chronic mucocutaneous candidiasis associated with other autoimmune manifestations developed over the years. The presence of the homozygous R257X mutation of the AIRE gene confirmed the diagnosis of APECED syndrome. We further performed literature review in 23 published Turkish APECED patients and noted that Finnish major mutation R257X is common in Turks. In particular, we assessed retrospectively how often the Ferre/Lionakis criteria would have resulted in earlier diagnosis in Finns, Sardinians and Turks in respect to the classic criteria. Since an earlier diagnosis could have been possible in 18.8% of Turkish, in 23.8% of Sardinian and 38.55% of Finnish patients we reviewed from literature, Ferre/Lionakis criteria could indeed allow in future earlier initiation of immunomodulatory treatments, if found effective in future studies.

  • YB-1 increases glomerular, but decreases interstitial fibrosis in CNI-induced nephropathy
    Clin. Immunol. (IF 3.557) Pub Date : 2018-07-03
    Lydia Gibbert, Daniela Hermert, Jialin Wang, Daniel Breitkopf, Christina Alidousty, Matthias Neusser, Clemens D. Cohen, Elisabeth Gröne, Iris Macheleidt, Thomas Rauen, Gerald S. Braun, Jürgen Floege, Tammo Ostendorf, Ute Raffetseder

    Calcineurin inhibitors (CNIs) are a cornerstone of the current treatment in solid organ transplantation and autoimmune disease. However, CNIs also bear deleterious effects as they cause glomerular and tubulointerstitial fibrosis in the kidney. We recently identified Y-box protein-1 (YB-1) as a novel downstream effector of CNI-signaling in the cytoplasm of glomerular cells. In the present study, we corroborate the pro-fibrotic role of YB-1 in glomeruli of patients under CNI-treatment. Such effects in glomeruli are significantly mitigated in CNI-treated mice with half-normal YB-1 expression (Yb1+/−). Surprisingly, in the tubulointerstitium we observe an opposite role of the CNI-YB-1 axis. Here, YB-1 is predominantly located to the nuclei and represses transcription of several extracellular matrix genes. Consistently, CNI-treatment in Yb1+/ mice markedly increases pro-fibrotic changes in the tubulointerstitium. In summary, our data provide evidence that fibrotic CNI-induced YB-1 effects in glomerular cells need to be contrasted with beneficial anti-fibrotic effects in the tubulointerstitium.

  • Single-cell epigenetics – Chromatin modification atlas unveiled by mass cytometry
    Clin. Immunol. (IF 3.557) Pub Date : 2018-06-28
    Peggie Cheung, Francesco Vallania, Mai Dvorak, Sarah E. Chang, Steven Schaffert, Michele Donato, Aditya Rao, Rong Mao, Paul J. Utz, Purvesh Khatri, Alex J. Kuo

    Modifications of histone proteins are fundamental to the regulation of epigenetic phenotypes. Dysregulations of histone modifications have been linked to the pathogenesis of diverse human diseases. However, identifying differential histone modifications in patients with immune-mediated diseases has been challenging, in part due to the lack of a powerful analytic platform to study histone modifications in the complex human immune system. We recently developed a highly multiplexed platform, Epigenetic landscape profiling using cytometry by Time-Of-Flight (EpiTOF), to analyze the global levels of a broad array of histone modifications in single cells using mass cytometry. In this review, we summarize the development of EpiTOF and discuss its potential applications in biomedical research. We anticipate that this platform will provide new insights into the roles of epigenetic regulation in hematopoiesis, immune cell functions and immune system aging, and reveal aberrant epigenetic patterns associated with immune-mediated diseases.

  • Both perforin and FasL are required for optimal CD8 T cell control of autoreactive B cells and autoantibody production in parent-into-F1 lupus mice
    Clin. Immunol. (IF 3.557) Pub Date : 2018-06-22
    Kateryna Soloviova, Maksym Puliaiev, Roman Puliaev, Irina Puliaeva, Charles S. Via

    To test the relative roles of perforin (pfp) vs. FasL in CTL control of autoreactive B cell expansion, we used the parent-into-F1 model of murine graft-vs.–host disease in which donor CD8 CTL prevent lupus like disease by eliminating activated autoreactive B cells. F1 mice receiving either pfp or FasL defective donor T cells exhibited an intermediate short-term phenotype. Pairing of purified normal CD4 T cells with either pfp or FasL defective CD8 T cell subsets resulted in impaired host B cell elimination and mild lupus like disease that was roughly equivalent in the two experimental groups. Thus, in addition to major roles in tumor and intracellular pathogen control, pfp mediated CD8 CTL killing plays a significant role in controlling autoreactive B cell expansion and lupus downregulation that is comparable to that mediated by FasL killing. Importantly, both pathways are required for optimal elimination of activated autoreactive B cells.

  • Interleukin-1 in monocyte activation phenotypes in systemic juvenile idiopathic arthritis: Observations from a clinical trial of rilonacept, an interleukin-1 inhibitor
    Clin. Immunol. (IF 3.557) Pub Date : 2018-06-19
    Yujuan Zhang, Saloni Gupta, Alexandra Ilstad-Minnihan, Sashi Ayyangar, Arielle D. Hay, Virginia Pascual, Norman T. Ilowite, Claudia Macaubas, Elizabeth D. Mellins

    Systemic juvenile idiopathic arthritis (sJIA) is a childhood rheumatic disease of unknown origin. Dysregulated innate immunity is implicated in disease pathology. We investigated if IL-1 inhibition affects circulating cytokines and monocyte gene expression. CD14+ monocytes from patients in the RAPPORT trial were analyzed by RT-PCR for expression of IL1B and transcription factors associated with monocyte activation. Serum IL-1ra decreased with treatment, and IL-18BP transiently increased. Serum levels of IL-1β, IL-6, IL-10 and IL-18 were unchanged. IRF5 and STAT6 were decreased, and PPARG was increased, independent of clinical response, and may represent a skew toward a PPARG-driven M2-like phenotype. IL1B expression was decreased in early clinical responders. A transient increase in STAT1, and a decrease in SOCS1 preceded the reduction in IL1B in early clinical responders. Changes in IL1B/STAT1/SOCS1 could be associated with crosstalk between IL-1 and IFN pathways in sJIA. These transcriptional changes might be useful as drug response biomarkers.

  • Involvement of CD8+ T cell subsets in early response to vascular injury in patients with peripheral arterial disease in vivo
    Clin. Immunol. (IF 3.557) Pub Date : 2018-06-21
    Pawel Maga, Tomasz P. Mikolajczyk, Lukasz Partyka, Mateusz Siedlinski, Mikolaj Maga, Marek Krzanowski, Krzysztof Malinowski, Kevin Luc, Rafal Nizankowski, Deepak L. Bhatt, Tomasz J. Guzik

    Aims Adaptive immunity is critical in vascular remodelling following arterial injury. We hypothesized that acute changes in T cells at a percutaneous transluminal angioplasty (PTA) site could serve as an index of their potential interaction with the injured vascular wall. Methods and Results T cell subsets were characterised in 45 patients with Rutherford 3–4 peripheral arterial disease (PAD) undergoing PTA. Direct angioplasty catheter blood sampling was performed before and immediately after the procedure. PTA was associated with an acute reduction of α/β-TcR CD8+ T cells. Further characterisation revealed significant reduction in pro-atherosclerotic CD28nullCD57+ cells, effector and effector memory cells, in addition to cells bearing activation and tissue homing/adhesion markers. Conclusions The acute reduction observed here is likely due to the adhesion of cells to the injured vascular wall, suggesting that immunosenescent, activated effector CD8+ cells have a role in the early vascular injury immune response following PTA in PAD patients.

  • A potentially important role for t cells and regulatory t cells in Langerhans cell histiocytosis
    Clin. Immunol. (IF 3.557) Pub Date : 2018-06-18
    Jenée M. Mitchell, Stuart P. Berzins, George Kannourakis

    Langerhans cell histiocytosis is characterized by lesions containing inflammatory immune cells, including myeloid cells and T cells. Patient mortality remains unacceptably high and new treatment options are required. Several LCH studies have identified aberrant frequencies of T cell subsets with potential immune regulatory properties. High numbers of Foxp3+ regulatory T cells and gamma-delta T cells have been reported in patients with LCH, although, the cause of their presence or their significance is not yet clear. This review describes the current understanding of how LCH develops and progresses, focusing on the growing evidence that regulatory T cell subsets may be important and discussing the exciting potential for harnessing these cells to treat LCH using immune based therapies.

  • Mechanisms of fibronectin-binding protein A (FnBPA110–263) vaccine efficacy in Staphylococcus aureus sepsis versus skin infection
    Clin. Immunol. (IF 3.557) Pub Date : 2018-06-12
    Rui Zhang, Sun Li, Xiao-Kai Zhang, Yu Wang, Liu-Yang Yang, Hao Zeng, Da-Peng Yan, Quan-Ming Zou, Qian-Fei Zuo

    Increasing rates of life-threatening infections and decreasing susceptibility to antibiotics urge an effective vaccine targeting Staphylococcus aureus. Here we investigate the role of cellular immunity in FnBPA110–263 mediated protection in Staphylococcus aureus infection. This study revealed FnBPA110–263 broadly protected mice from seven FnBPA isotypes strains in the sepsis model. FnBPA110–263 immunized B-cell deficient mice were protected against lethal challenge, while T-cell deficient mice were not. Reconstituting mice with FnBPA110–263 specific CD4+ T-cells conferred antigen specific protection. In vitro assays indicated that isolated FnBPA110–263 specific splenocytes from immunized mice produced abundant IL-17A. IL-17A deficient mice were not protected from a lethal challenge by FnBPA110–263 vaccination. Moreover, neutralizing IL-17A, but not IFN-γ,reverses FnBPA110–263-induced protective efficacy in sepsis and skin infection model. These findings suggest that IL-17A producing Th17 cells play an essential role in FnBPA110–263 vaccine-mediated defense against S. aureus sepsis and skin infection in mice.

  • Association of high 5-hydroxymethylcytosine levels with Ten Eleven Translocation 2 overexpression and inflammation in Sjögren's syndrome patients
    Clin. Immunol. (IF 3.557) Pub Date : 2018-06-09
    Carolina Lagos, Patricia Carvajal, Isabel Castro, Daniela Jara, Sergio González, Sergio Aguilera, María-José Barrera, Andrew F.G. Quest, Verónica Bahamondes, Claudio Molina, Ulises Urzúa, Marcela A. Hermoso, Cecilia Leyton, María-Julieta González

    Here, we determined the 5-hydroxymethylcytosine (5hmC), 5-methylcytosine (5mC), Ten Eleven Translocation (TETs), and DNA methyltransferases (DNMTs) levels in epithelial and inflammatory cells of labial salivary glands (LSG) from Sjögren's syndrome (SS)-patients and the effect of cytokines on HSG cells. LSG from SS-patients, controls and HSG cells incubated with cytokines were analysed. Levels of 5mC, 5hmC, DNMTs, TET2 and MeCP2 were assessed by immunofluorescence. In epithelial cells from SS-patients, an increase in TET2, 5hmC and a decrease in 5mC and MeCP2 were observed, additionally, high levels of 5mC and DNMTs and low levels of 5hmC were detected in inflammatory cells. Cytokines increased TET2 and 5hmC and decreased 5mC levels. Considering that the TET2 gene.promoter contains response elements for transcription factors activated by cytokines, together to in vitro results suggest that changes in DNA hydroxymethylation, resulting from altered levels of TET2 are likely to be relevant in the Sjögren's syndrome etiopathogenesis.

  • Effect of high glucose on cytokine production by human peripheral blood immune cells and type I interferon signaling in monocytes: Implications for the role of hyperglycemia in the diabetes inflammatory process and host defense against infection
    Clin. Immunol. (IF 3.557) Pub Date : 2018-06-09
    Ronghua Hu, Chang-Qing Xia, Edward Butfiloski, Michael Clare-Salzler

    The major metabolic feature of diabetes is hyperglycemia which has been linked to the diabetes inflammatory processes, and diabetes-related vulnerability to infection. In the present study, we assessed how glucose affected PBMCs in type I interferon (IFN) production and subsequent signaling. We found that the moderately elevated glucose promoted, and high glucose suppressed type I IFN production, respectively. Pre-exposure to high glucose rendered monocytes more sensitive to IFN-α stimulation with heightened signaling, whereas, instantaneous addition of high glucose did not exhibit such effect. Consistent with this finding, the mRNA levels of IFN-α-induced IRF-7 in PBMCs were positively correlated with HbA1c levels of diabetes patients. Additionally, we found that high glucose promoted the production of other proinflammatory cytokines/chemokines. This study suggests that hyperglycemia may affect the inflammatory process in diabetes via promoting proinflammatory cytokines, as well as the host defense against microbial infections through impeding type I IFN production and signaling.

  • Residual T cell activation and skewed CD8+ T cell memory differentiation despite antiretroviral therapy-induced HIV suppression
    Clin. Immunol. (IF 3.557) Pub Date : 2018-06-05
    Ramla F. Tanko, Andreia P. Soares, Lindi Masson, Nigel J. Garrett, Natasha Samsunder, Quarraisha Abdool Karim, Salim S. Abdool Karim, Catherine Riou, Wendy A. Burgers

    HIV infection results in excessive T cell activation and dysfunction which may persist even during effective antiretroviral therapy (ART). The dynamics of immune ‘deactivation’ and extent to which T cell memory subsets normalize after ART are unclear. We longitudinally assessed the influence of 1 year of ART on the phenotype of T cells in HIV-infected African women, relative to matched HIV-uninfected women, using activation (CD38, HLA-DR) and differentiation markers (CD27, CD45RO). ART induced a substantial reduction in T cell activation, but remained higher than HIV-uninfected controls. ART largely normalized the distribution of CD4+ T cell memory subsets, while the distribution of CD8+ T cell memory subsets remained significantly skewed compared to HIV-uninfected individuals. Thus, there was a considerable but only partial reversal of T cell defects upon ART. Understanding T cell impairment may provide important insights into mechanisms of HIV pathogenesis in the era of ART.

  • Enhanced activation of circulating plasmacytoid dendritic cells in patients with Chronic Obstructive Pulmonary Disease and experimental smoking-induced emphysema
    Clin. Immunol. (IF 3.557) Pub Date : 2017-11-08
    Shi-lin Qiu, Liang-jian Kuang, Qi-ya Tang, Min-chao Duan, Jing Bai, Zhi-yi He, Jian-quan Zhang, Mei-hua Li, Jing-min Deng, Guang-nan Liu, Xiao-ning Zhong

    Plasmacytoid dendritic cells (pDCs) are key cells bridging the innate with adaptive immunity. However, the phenotypic characteristics of circulating pDCs and its role in smoking related-Chronic Obstructive Pulmonary Disease (COPD) remain largely unknown. The aim of this study was analyzed the phenotype of circulating pDCs and the expression of IFN-γ producing CD8+ T cells and IL-17-producing CD8+ T cells in patients with COPD by using multi-colour flow cytometry. The cytokine profiles in peripheral blood from all subjects were measured by ELISA. The influence of cigarette smoke on pDCs was evaluated in an experimental mouse model of emphysema. Circulating pDCs in patients with COPD and in mice exposed to cigarette smoke expressed high levels of co-stimulatory molecules CD40 or CD86 accompanied by exaggerated IFN-γ producing CD8+ T cells and IL-17-producing CD8+ T cells. In vitro, cigarette smoke directly promoted pDCs maturation and release of IFN-α, IL-6 and IL-12, subsequently inducing differentiation of IFN-γ producing CD8+ T cells and IL-17-producing CD8+ T cells from mouse naïve CD8+ T cells. These data suggested that circulating pDCs display an enhanced activation phenotype in patients with COPD and in experimental smoking mouse model of emphysema, which might contribute to exaggerated IFN-γ producing CD8+ T and IL-17-producing CD8+ T cell-mediated immune responses.

  • Novel anti-suprabasin antibodies may contribute to the pathogenesis of neuropsychiatric systemic lupus erythematosus
    Clin. Immunol. (IF 3.557) Pub Date : 2017-11-21
    Kunihiro Ichinose, Kaname Ohyama, Kaori Furukawa, Osamu Higuchi, Akihiro Mukaino, Katsuya Satoh, Shunya Nakane, Toshimasa Shimizu, Masataka Umeda, Shoichi Fukui, Ayako Nishino, Hideki Nakajima, Tomohiro Koga, Shin-ya Kawashiri, Naoki Iwamoto, Mami Tamai, Hideki Nakamura, Tomoki Origuchi, Atsushi Kawakami

    Neuropsychiatric systemic lupus erythematosus (NPSLE) is often difficult to diagnose and distinguish from other diseases, because no NPSLE-specific antibodies have been identified. We developed a novel proteomic strategy for identifying and profiling antigens in immune complexes in the cerebrospinal fluid (CSF), and applied this strategy to 26 NPSLE patients. As controls, we also included 25 SLE patients without neuropsychiatric manifestations (SLE), 15 with relapsing remitting multiple sclerosis (MS) and 10 with normal pressure hydrocephalus (NPH). We identified immune complexes of suprabasin (SBSN) in the CSF of the NPSLE group. The titer of anti-SBSN antibodies was significantly higher in the CSF of the NPSLE group compared to those of the SLE, MS and NPH groups. Microarray data showed that the senescence and autophagy pathways were significantly changed in astrocytes exposed to anti-SBSN antibodies. Our findings indicate that SBSN could be a novel autoantibody for the evaluation of suspected NPSLE.

  • Citrullinated fibrinogen impairs immunomodulatory function of bone marrow mesenchymal stem cells by triggering toll-like receptor
    Clin. Immunol. (IF 3.557) 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 CC 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.

  • Thymopoiesis following HSCT; a retrospective review comparing interventions for aGVHD in a pediatric cohort
    Clin. Immunol. (IF 3.557) 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.

  • Cisplatin inhibits the progression of bladder cancer by selectively depleting G-MDSCs: A novel chemoimmunomodulating strategy
    Clin. Immunol. (IF 3.557) 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.

  • Plasmablast antibody repertoires in elderly influenza vaccine responders exhibit restricted diversity but increased breadth of binding across influenza strains
    Clin. Immunol. (IF 3.557) 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.

  • Impaired X-CGD T cell compartment is gp91phox-NADPH oxidase independent
    Clin. Immunol. (IF 3.557) Pub Date : 2018-02-03
    Maria Chiriaco, Fabio Casciano, Gigliola Di Matteo, Berhard Gentner, Alessia Claps, Silvia Di Cesare, Nicola Cotugno, Patrizia D'Argenio, Paolo Rossi, Alessandro Aiuti, Andrea Finocchi

    Chronic granulomatous disease (CGD) is a phagocytic disorder characterized by a defective production of reactive oxygen species (ROSs). 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 had a skewed TCRV-beta distribution in CD8+ T cells, particularly in older patients, and a reduced proliferative responses toward mitogens compared to healthy donors (HD). 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 when forcing gp91phox expression transducing T cells from X-CGD and HD with a SIN lentiviral vector (LVV) encoding the gp91phox cDNA.

  • Epigenetic editing: How cutting-edge targeted epigenetic modification might provide novel avenues for autoimmune disease therapy
    Clin. Immunol. (IF 3.557) 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.

  • Diminished antibody response to influenza vaccination is characterized by expansion of an age-associated B-cell population with low PAX5
    Clin. Immunol. (IF 3.557) 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.

  • Mechanistic aspects of epigenetic dysregulation in SLE
    Clin. Immunol. (IF 3.557) 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.

  • Dysfunction of CD3−CD16+CD56dim and CD3−CD16−CD56bright NK cell subsets in RR-MS patients
    Clin. Immunol. (IF 3.557) 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. 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. These findings support the possible contribution of NK cells to RR-MS immuno-pathogenesis.

  • A novel PADRE-Kv1.3 vaccine effectively induces therapeutic antibodies and ameliorates experimental autoimmune encephalomyelitis in rats
    Clin. Immunol. (IF 3.557) 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.

  • Treatment of antiphospholipid syndrome beyond anticoagulation
    Clin. Immunol. (IF 3.557) 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.

  • Epigenetic interplay between immune, stromal and cancer cells in the tumor microenvironment
    Clin. Immunol. (IF 3.557) 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.

  • Contribution of MTHFR gene variants in lupus related subclinical atherosclerosis
    Clin. Immunol. (IF 3.557) 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 (MTHFR) 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 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 MTHFR 677TT 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]. MTHFR 677TT 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 MTHFR 677TT 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.

  • Biological therapies in inflammatory bowel disease: Beyond anti-TNF therapies
    Clin. Immunol. (IF 3.557) 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.

  • Epigenetics as biomarkers in autoimmune diseases
    Clin. Immunol. (IF 3.557) 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.

  • Epigenome-wide association studies for systemic autoimmune diseases: The road behind and the road ahead
    Clin. Immunol. (IF 3.557) 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 associations 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.

  • Circulating integrin alpha4/beta7+ lymphocytes targeted by vedolizumab have a pro-inflammatory phenotype ☆
    Clin. Immunol. (IF 3.557) Pub Date : 2018-05-26
    James D. Lord, S. Alice Long, Donna M. Shows, Jerill Thorpe, Katherine Schwedhelm, Janice Chen, Mariko Kita, Jane H. Buckner

    Integrin alpha4/beta7 on circulating lymphocytes identifies them as gut-tropic, and can be targeted by the humanized antibody vedolizumab to treat inflammatory bowel disease (IBD). We found lymphocytes expressing alpha4/beta7 were significantly more responsive to the pro-inflammatory cytokines IL-6, IL-7, and IL-21, and less responsive to the regulatory T cell (Treg)-supporting cytokine IL-2. Alpha4/beta7 was expressed by a smaller percent of FOXP3 + Helios+ thymically-derived Tregs (tTregs) than FOXP3 + Helios- peripherally-derived Tregs (pTregs) or FOXP3- effector T cells. Integrin alpha4/beta7+ CD4 T cells were also rare among cells expressing the Th2 marker CRTh2, but enriched in cells bearing the circulating T follicular helper cell marker CXCR5. Thus the effect of this anti-integrin therapy on the mucosal immune system may be more qualitative than quantitative, and selectively replace pro-inflammatory effector cells with Tregs and Th2 cells to facilitate immune tolerance in the mucosa without globally depleting lymphocytes from the intestinal mucosa.

  • Combination of anti-citrullinated protein antibodies and rheumatoid factor is associated with increased systemic inflammatory mediators and more rapid progression from preclinical to clinical rheumatoid arthritis
    Clin. Immunol. (IF 3.557) Pub Date : 2018-05-26
    Nithya Lingampalli, Jeremy Sokolove, Lauren J. Lahey, Jess D. Edison, William R. Gilliland, V. Michael Holers, Kevin D. Deane, William H. Robinson

    The development of rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPAs) can be observed years prior to clinical diagnosis of rheumatoid arthritis (RA). Nevertheless, the interaction between these two autoantibodies and their combined effect on development of RA is unclear. We measured RF, cytokines, and ACPA subtypes in serial pre-clinical serum samples collected from 83 US veterans who all developed RA. Levels of cytokines and ACPAs were compared between the following groups: anti-cyclic citrullinated peptide (anti-CCP)-/RF- (double negative), anti-CCP+/RF-, anti-CCP-/RF+, or anti-CCP+/RF+ (double-positive). The double-positive subgroup had significantly higher levels of 20 inflammatory cytokines and 29 ACPA reactivities, and the shortest interval, 1.3 years, between the preclinical sample timepoint and diagnosis of RA. Thus, the combined presence of ACPAs and RF is associated with a more rapid progression to RA, suggesting that anti-CCP+/RF+ individuals have a more advanced preclinical disease state and that the onset of RA may be imminent.

  • Improved synaptic and cognitive function in aged 3 × Tg-AD mice with reduced amyloid-β after immunotherapy with a novel recombinant 6Aβ15-TF chimeric vaccine
    Clin. Immunol. (IF 3.557) Pub Date : 2018-05-24
    Yun-Zhou Yu, Qing-Li Li, Hai-Chao Wang, Si Liu, Xiao-Bin Pang, Qing Xu, Xiao-Wei Zhou, Pei-Tang Huang
  • An anti-NMDA receptor encephalitis mimicking an HIV encephalitis
    Clin. Immunol. (IF 3.557) 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.

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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