当前期刊: Genes and Immunity Go to current issue    加入关注   
显示样式:        排序: 导出
  • Analysis of the genetic variants associated with circulating levels of sgp130. Results from the IMPROVE study
    Genes. Immun. (IF 2.631) Pub Date : 2020-01-14
    Alice Bonomi; Fabrizio Veglia; Damiano Baldassarre; Rona J. Strawbridge; Zahra Golabkesh; Bengt Sennblad; Karin Leander; Andries J. Smit; Philippe Giral; Steve E. Humphries; Elena Tremoli; Anders Hamsten; Ulf de Faire; Bruna Gigante
  • 更新日期:2020-01-13
  • A SNP upstream of the cyclic GMP-AMP synthase (cGAS) gene protects from relapse and extra-pulmonary TB and relates to BCG vaccination status in an Indian cohort
    Genes. Immun. (IF 2.631) Pub Date : 2019-05-23
    Shruthi Thada, Sanne Burkert, Ramya Sivangala, Abid Hussain, Saubashya Sur, Nickel Dittrich, Melanie L. Conrad, Hortense Slevogt, Suman Latha Gaddam, Ralf R. Schumann
  • MiR-4295 facilitates cell proliferation and metastasis in head and neck squamous cell carcinoma by targeting NPTX1
    Genes. Immun. (IF 2.631) Pub Date : 2019-05-23
    Shun Lu, Cheng Zhou, Bingwen Zou, Hanyi Zhang, Mei Feng
  • Inhibitor of apoptosis proteins in human health and disease
    Genes. Immun. (IF 2.631) Pub Date : 2019-05-21
    Matous Hrdinka, Monica Yabal
  • CARving up colorectal cancer organoids in vitro
    Genes. Immun. (IF 2.631) Pub Date : 2019-05-20
    Christian M. Schürch
  • Relationship between human leukocyte antigen alleles and risk of Kaposi’s sarcoma in Cameroon
    Genes. Immun. (IF 2.631) Pub Date : 2019-05-20
    Elena M. Cornejo Castro, Brian J. Morrison, Vickie A. Marshall, Nazzarena Labo, Wendell J. Miley, Nathan Clements, George Nelson, Paul Ndom, Kristen Stolka, Jennifer J. Hemingway-Foday, Mahamat Abassora, Xiaojiang Gao, Jennifer S. Smith, Mary Carrington, Denise Whitby
  • MHC haplotype diversity in Icelandic horses determined by polymorphic microsatellites
    Genes. Immun. (IF 2.631) Pub Date : 2019-05-09
    Camille M. Holmes, Nathaniel Violette, Donald Miller, Bettina Wagner, Vilhjálmur Svansson, Douglas F. Antczak
  • Correction: HLA-C*07 in axial spondyloarthritis: data from the German Spondyloarthritis Inception Cohort and the Spondyloarthritis Caught Early cohort
    Genes. Immun. (IF 2.631) Pub Date : 2019-05-09
    Janneke J. de Winter, Iris C. Blijdorp, Henriëtte M. de Jong, Jürgen Sauter, Alexander H. Schmidt, Floris A. van Gaalen, Désirée van der Heijde, Denis Poddubnyy, Nataliya G. Yeremenko, Marleen G. van de Sande, Dominique L. Baeten

    The original version of this Article contained an error in the spelling of the author Denis Poddubnyy, which was incorrectly given as Denis Podubbnyy. This has now been corrected in both the PDF and HTML versions of the Article.

  • 更新日期:2019-11-18
  • Novel mechanistic insights into physiological signaling pathways mediated by mycobacterial Ser/Thr protein kinases
    Genes. Immun. (IF 2.631) Pub Date : 2019-04-25
    Marco Bellinzoni, Anne Marie Wehenkel, Rosario Durán, Pedro M. Alzari
  • 更新日期:2019-11-18
  • The remarkable history of the hepatitis C virus
    Genes. Immun. (IF 2.631) Pub Date : 2019-04-25
    Stanislas Pol, Sylvie Lagaye
  • Studying fungal pathogens of humans and fungal infections: fungal diversity and diversity of approaches
    Genes. Immun. (IF 2.631) Pub Date : 2019-04-25
    Guilhem Janbon, Jessica Quintin, Fanny Lanternier, Christophe d’Enfert

    Seminal work by Louis Pasteur revealed the contribution of fungi—yeasts and microsporidia to agroindustry and disease in animals, respectively. More than 150 years later, the impact of fungi on human health and beyond is an ever-increasing issue, although often underestimated. Recent studies estimate that fungal infections, especially those caused by Candida, Cryptococcus and Aspergillus species, kill more than one million people annually. Indeed, these neglected infections are in general very difficult to cure and the associated mortality remains very high even when antifungal treatments exist. The development of new antifungals and diagnostic tools that are both necessary to fight fungal diseases efficiently, requires greater insights in the biology of the fungal pathogens of humans in the context of the infection, on their epidemiology, and on their role in the human mycobiota. We also need a better understanding of the host immune responses to fungal pathogens as well as the genetic basis for the increased sensitivity of some individuals to fungal infections. Here, we highlight some recent progress made in these different areas of research, in particular based on work conducted in our own laboratories. These progress should lay the ground for better management of fungal infections, as they provide opportunities for better diagnostic, vaccination, the development of classical antifungals but also strategies for targeting virulence factors or the host.

  • 更新日期:2019-11-18
  • Yersinia pestis and plague: an updated view on evolution, virulence determinants, immune subversion, vaccination, and diagnostics
    Genes. Immun. (IF 2.631) Pub Date : 2019-04-03
    Christian E. Demeure, Olivier Dussurget, Guillem Mas Fiol, Anne-Sophie Le Guern, Cyril Savin, Javier Pizarro-Cerdá
  • Duclaux, Chamberland, Roux, Grancher, and Metchnikoff: the five musketeers of Louis Pasteur
    Genes. Immun. (IF 2.631) Pub Date : 2019-03-29
    Jean-Marc Cavaillon, Sandra Legout
  • From septicemia to sepsis 3.0—from Ignaz Semmelweis to Louis Pasteur
    Genes. Immun. (IF 2.631) Pub Date : 2019-03-22
    Jean-Marc Cavaillon, Fabrice Chrétien
  • The transcriptional profile of circulating myeloid derived suppressor cells correlates with tumor development and progression in mouse
    Genes. Immun. (IF 2.631) Pub Date : 2019-03-18
    Ido Nachmany, Yoel Bogoch, Gilgi Friedlander-Malik, Omer Amar, Ekaterina Bondar, Nitzan Zohar, Shay Hantisteanu, Ofer Fainaru, Nir Lubezky, Joseph M. Klausner, Niv Pencovich
  • HLA-C*07 in axial spondyloarthritis: data from the German Spondyloarthritis Inception Cohort and the Spondyloarthritis Caught Early cohort
    Genes. Immun. (IF 2.631) Pub Date : 2019-02-26
    Janneke J. de Winter, Iris C. Blijdorp, Henriëtte M. de Jong, Jürgen Sauter, Alexander H. Schmidt, Floris A. van Gaalen, Désirée van der Heijde, Denis Poddubnyy, Nataliya G. Yeremenko, Marleen G. van de Sande, Dominique L. Baeten
  • Prioritizing Crohn’s disease genes by integrating association signals with gene expression implicates monocyte subsets
    Genes. Immun. (IF 2.631) Pub Date : 2019-01-29
    Kyle Gettler, Mamta Giri, Ephraim Kenigsberg, Jerome Martin, Ling-Shiang Chuang, Nai-Yun Hsu, Lee A. Denson, Jeffrey S. Hyams, Anne Griffiths, Joshua D. Noe, Wallace V. Crandall, David R. Mack, Richard Kellermayer, Clara Abraham, Gabriel Hoffman, Subra Kugathasan, Judy H. Cho
  • Extra-adrenal glucocorticoid synthesis at epithelial barriers
    Genes. Immun. (IF 2.631) Pub Date : 2019-01-29
    Truong San Phan, Verena M. Merk, Thomas Brunner
  • The many faces of tumor necrosis factor signaling in the intestinal epithelium
    Genes. Immun. (IF 2.631) Pub Date : 2019-01-28
    M. Eugenia Delgado, Thomas Brunner
  • Intestinal glucocorticoid synthesis enzymes in pediatric inflammatory bowel disease patients
    Genes. Immun. (IF 2.631) Pub Date : 2019-01-28
    Asma Ahmed, Juliane Schwaderer, Annika Hantusch, Kaija-Leena Kolho, Thomas Brunner
  • Mother−child histocompatibility and risk of rheumatoid arthritis and systemic lupus erythematosus among mothers
    Genes. Immun. (IF 2.631) Pub Date : 2019-01-12
    Giovanna I. Cruz, Xiaorong Shao, Hong Quach, Diana Quach, Kimberly A. Ho, Kirsten Sterba, Janelle A. Noble, Nikolaos A. Patsopoulos, Michael P. Busch, Darrell J. Triulzi, Nektarios Ladas, Rainer Blasczyk, Wendy S. W. Wong, Benjamin D. Solomon, John E. Niederhuber, Lindsey A. Criswell, Lisa F. Barcellos

    The study objective was to test the hypothesis that having histocompatible children increases the risk of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), possibly by contributing to the persistence of fetal cells acquired during pregnancy. We conducted a case control study using data from the UC San Francisco Mother Child Immunogenetic Study and studies at the Inova Translational Medicine Institute. We imputed human leukocyte antigen (HLA) alleles and minor histocompatibility antigens (mHags). We created a variable of exposure to histocompatible children. We estimated an average sequence similarity matching (SSM) score for each mother based on discordant mother−child alleles as a measure of histocompatibility. We used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals. A total of 138 RA, 117 SLE, and 913 control mothers were analyzed. Increased risk of RA was associated with having any child compatible at HLA-B (OR 1.9; 1.2–3.1), DPB1 (OR 1.8; 1.2–2.6) or DQB1 (OR 1.8; 1.2–2.7). Compatibility at mHag ZAPHIR was associated with reduced risk of SLE among mothers carrying the HLA-restriction allele B*07:02 (n = 262; OR 0.4; 0.2–0.8). Our findings support the hypothesis that mother−child histocompatibility is associated with risk of RA and SLE.

  • The FCGR2C allele that modulated the risk of HIV-1 infection in the Thai RV144 vaccine trial is implicated in HIV-1 disease progression
    Genes. Immun. (IF 2.631) Pub Date : 2018-12-19
    Ria Lassaunière, Maria Paximadis, Osman Ebrahim, Richard E. Chaisson, Neil A. Martinson, Caroline T. Tiemessen
  • Cell death pathologies: targeting death pathways and the immune system for cancer therapy
    Genes. Immun. (IF 2.631) Pub Date : 2018-12-19
    Francesca Pentimalli, Sandro Grelli, Nicola Di Daniele, Gerry Melino, Ivano Amelio
  • Unfolding of hidden white blood cell count phenotypes for gene discovery using latent class mixed modeling
    Genes. Immun. (IF 2.631) Pub Date : 2018-11-21
    Taryn O. Hall, Ian B. Stanaway, David S. Carrell, Robert J. Carroll, Joshua C. Denny, Hakon Hakonarson, Eric B. Larson, Frank D. Mentch, Peggy L. Peissig, Sarah A. Pendergrass, Elisabeth A. Rosenthal, Gail P. Jarvik, David R. Crosslin
  • Prognostic role of the systemic immune-inflammation index in brain metastases from lung adenocarcinoma with different EGFR mutations
    Genes. Immun. (IF 2.631) Pub Date : 2018-11-09
    Hongwei Li, Guochao Wang, Huanhu Zhang, Xin Song, Jianzhong Cao, Xiaqin Zhang, Ruiqi Xue, Weili Wang, Sufang Jia, Zhengran Li
  • An IL7RA exon 5 polymorphism is associated with impaired IL-7Rα splicing and protection against tuberculosis in Ghana
    Genes. Immun. (IF 2.631) Pub Date : 2018-10-31
    Christian Lundtoft, Anthony Afum-Adjei Awuah, Alptekin Güler, Kirstin Harling, Heiner Schaal, Ertan Mayatepek, Richard O. Phillips, Norman Nausch, Ellis Owusu-Dabo, Marc Jacobsen
  • Cell death in cancer in the era of precision medicine
    Genes. Immun. (IF 2.631) Pub Date : 2018-10-19
    Giuseppe Raschellà, Gerry Melino, Alessandra Gambacurta
  • Ecto-Calreticulin is essential for an efficient immunogenic cell death stimulation in mouse melanoma
    Genes. Immun. (IF 2.631) Pub Date : 2018-10-04
    Paola Giglio, Mara Gagliardi, Roberta Bernardini, Maurizio Mattei, Diego Cotella, Claudio Santoro, Mauro Piacentini, Marco Corazzari
  • Polymorphism of FCGR3A gene in chronic beryllium disease
    Genes. Immun. (IF 2.631) Pub Date : 2018-09-24
    Bing Liu, Lisa A. Maier, Nabeel Hamzeh, Kristyn MacPhail, Margaret M. Mroz, Hongbo Liu, Li Li
  • System network analysis of genomics and transcriptomics data identified type 1 diabetes-associated pathway and genes
    Genes. Immun. (IF 2.631) Pub Date : 2018-09-24
    Jun-Min Lu, Yuan-Cheng Chen, Zeng-Xin Ao, Jie Shen, Chun-Ping Zeng, Xu Lin, Lin-Ping Peng, Rou Zhou, Xia-Fang Wang, Cheng Peng, Hong-Mei Xiao, Kun Zhang, Hong-Wen Deng
  • Primary immunodeficiency diseases in a tuberculosis endemic region: challenges and opportunities
    Genes. Immun. (IF 2.631) Pub Date : 2018-09-06
    Brigitte Glanzmann, Caitlin Uren, Nikola de Villiers, Ansia van Coller, Richard H. Glashoff, Michael Urban, Eileen G. Hoal, Monika M. Esser, Marlo Möller, Craig J. Kinnear
  • MICA and NKG2D variants as risk factors in spondyloarthritis: a case–control study
    Genes. Immun. (IF 2.631) Pub Date : 2018-09-04
    Marie Fechtenbaum, Judith Desoutter, Gauthier Delvallez, Etienne Brochot, Nicolas Guillaume, Vincent Goëb

    The major histocompatibility complex class I polypeptide-related sequence A (MICA) glycoprotein mediates the activation of the natural killer group 2D receptor (NKG2D) expressed on NK and CD8+ T cells. A methionine or valine at position 129 in exon 3 results in strong (MICA129 met) or weak (MICA129 val) binding to NKG2D. The MICA A5.1 allele causes a premature stop codon. Various NKG2D polymorphisms are associated with low (NKC3 C/C and NKC4 C/C) or high (NKC3 G/G and NKC4 T/T) levels of NK cell cytotoxic activity. In 162 patients with spondyloarthritis (115 with ankylosing spondyloarthritis, 46 with psoriatic arthritis and 1 with reactive arthritis) compared to 124 healthy controls, MICA-129 with methionine allele was more frequent in patients with spondyloarthritis (odds ratio (OR) (95% confidence interval) = 4.84 (2.75‒8.67)), whereas MICA-129 val/val, MICA A5.1 and NKC3 C/C variants were less frequent (OR = 0.20 (0.11‒0.37), 0.15 (0.06‒0.36) and 0.24 (0.13‒0.44), respectively). After adjustment for HLA-B*27 status, only NKC3 C/C remained linked to spondyloarthritis (adjusted OR = 0.14 (0.06‒0.33)). Homozygosity for MICA A5.1 is linked to ankylosing spondyloarthritis, and NKC3 C/C and MICA-129 val/val to psoriatic arthritis. MICA and NKC3 polymorphisms (related to a low NK cell cytotoxic activity) constituted a genetic association with spondyloarthritis.

  • Association between thyroglobulin polymorphisms and autoimmune thyroid disease: a systematic review and meta-analysis of case–control studies
    Genes. Immun. (IF 2.631) Pub Date : 2018-08-24
    Ming-Liang Zhang, Dong-ming Zhang, Cai-E. Wang, Xiao-Long Chen, Fang-Zhou Liu, Jian-Xue Yang
  • Fine-mapping analysis of a chromosome 2 region linked to resistance to Mycobacterium tuberculosis infection in Uganda reveals potential regulatory variants
    Genes. Immun. (IF 2.631) Pub Date : 2018-08-13
    Robert P. Igo, Noémi B. Hall, LaShaunda L. Malone, Jacob B. Hall, Barbara Truitt, Feiyou Qiu, Li Tao, Ezekiel Mupere, Audrey Schnell, Thomas R. Hawn, William S. Bush, Moses Joloba, W. Henry Boom, Catherine M. Stein
  • Correction: Association between interleukin family gene polymorphisms and recurrent aphthous stomatitis risk
    Genes. Immun. (IF 2.631) Pub Date : 2018-07-09
    Ying Zhou, Jun Wu, Wei Wang, Mingfang Sun

    The original version of this article omitted the corresponding author Mingfang Sun and the author Ying Zhou from the Division of Rheumatology, Research Institute of Surgery, Daping Hospital, the Army Medical University, Chongqing 400042, China. This has now been corrected in the PDF and HTML versions of the article.

  • Genes at human chromosome 5q31.1 regulate delayed-type hypersensitivity responses associated with Leishmania chagasi infection.
    Genes. Immun. (IF 2.631) Pub Date : 2007-08-24
    S M B Jeronimo,A K B Holst,S E Jamieson,R Francis,D R A Martins,F L Bezerra,N A Ettinger,E T Nascimento,G R Monteiro,H G Lacerda,E N Miller,H J Cordell,P Duggal,T H Beaty,J M Blackwell,M E Wilson

    Visceral leishmaniasis (VL) caused by Leishmania chagasi is endemic to northeast Brazil. A positive delayed-type hypersensitivity skin test response (DTH+) is a marker for acquired resistance to disease, clusters in families and may be genetically controlled. Twenty-three single nucleotide polymorphisms (SNPs) were genotyped in the cytokine 5q23.3-q31.1 region IRF1-IL5-IL13-IL4-IL9-LECT2-TGFBI in 102 families (323 DTH+; 190 DTH-; 123 VL individuals) from a VL endemic region in northeast Brazil. Data from 20 SNPs were analyzed for association with DTH+/- status and VL using family-based, stepwise conditional logistic regression analysis. Independent associations were observed between the DTH+ phenotype and markers in separate linkage disequilibrium blocks in LECT2 (OR 2.25; P=0.005; 95% CI=1.28-3.97) and TGFBI (OR 1.94; P=0.003; 95% CI=1.24-3.03). VL child/parent trios gave no evidence of association, but the DTH- phenotype was associated with SNP rs2070874 at IL4 (OR 3.14; P=0.006; 95% CI=1.38-7.14), and SNP rs30740 between LECT2 and TGFBI (OR 3.00; P=0.042; 95% CI=1.04-8.65). These results indicate several genes in the immune response gene cluster at 5q23.3-q31.1 influence outcomes of L. chagasi infection in this region of Brazil.

  • Positive replication and linkage disequilibrium mapping of the chromosome 21q22.1 malaria susceptibility locus.
    Genes. Immun. (IF 2.631) Pub Date : 2007-08-19
    C C Khor,F O Vannberg,S J Chapman,A Walley,C Aucan,H Loke,N J White,T Peto,L K Khor,D Kwiatkowski,N Day,A Scott,J A Berkley,K Marsh,N Peshu,K Maitland,T N Williams,A V S Hill

    Four cytokine receptor genes are located on Chr21q22.11, encoding the alpha and beta subunits of the interferon-alpha receptor (IFNAR1 and IFNAR2), the beta subunit of the interleukin 10 receptor (IL10RB) and the second subunit of the interferon-gamma receptor (IFNGR2). We previously reported that two variants in IFNAR1 were associated with susceptibility to malaria in Gambians. We now present an extensive fine-scale mapping of the associated region utilizing 45 additional genetic markers obtained from public databases and by sequencing a 44 kb region in and around the IFNAR1 gene in 24 Gambian children (12 cases/12 controls). Within the IFNAR1 gene, a newly studied C --> G single-nucleotide polymorphism (IFNAR1 272354c-g) at position -576 relative to the transcription start was found to be more strongly associated with susceptibility to severe malaria. Association was observed in three populations: in Gambian (P=0.002), Kenyan (P=0.022) and Vietnamese (P=0.005) case-control studies. When all three studies were combined, using the Mantel-Haenszel test, the presence of IFNAR1 -576G was associated with a substantially elevated risk of severe malaria (N=2444, OR=1.38, 95% CI: 1.17-1.64; P=1.7 x 10(-4)). This study builds on previous work to further highlight the importance of the type-I interferon pathway in malaria susceptibility and illustrates the utility of typing SNPs within regions of high linkage disequilibrium in multiple populations to confirm initial positive associations.

  • IFNG and IFNGR1 gene polymorphisms and susceptibility to post-kala-azar dermal leishmaniasis in Sudan.
    Genes. Immun. (IF 2.631) Pub Date : 2006-12-01
    M A Salih,M E Ibrahim,J M Blackwell,E N Miller,E A G Khalil,A M ElHassan,A M Musa,H S Mohamed

    Post-kala-azar dermal leishmanaisis (PKDL) in Sudan is associated with elevated interferon-gamma (IFN-gamma). To study interferon-gamma pathways in PKDL, we genotyped 80 trios from the Masalit ethnic group for polymorphisms at -470 ins/delTT, -270T/C, -56T/C and +95T/C in IFNGR1 and at -179G/A and +874T/A in IFNG. No associations occurred at IFNG. Global association with haplotypes comprising all four markers at IFNGR1 (chi(2)(10df)=21.97, P=0.015) was observed, associated with a significant (chi(2)(1df)=4.54, P=0.033) bias in transmission of the haplotype insTT T T T and less (chi(2)(1df)=5.59, P=0.018) than expected transmission of insTT C C C. When compared with data on malaria associations from Gambia, the results suggest a complex pattern of haplotypic variation at the IFNGR1 promoter locus associated with different infectious disease in African populations that reflect the complex roles of IFN-gamma in parasite killing versus inflammation and pathogenesis.

  • Genome-wide scan for visceral leishmaniasis susceptibility genes in Brazil.
    Genes. Immun. (IF 2.631) Pub Date : 2006-11-24
    S E Jamieson,E N Miller,C S Peacock,M Fakiola,M E Wilson,A Bales-Holst,M-A Shaw,F Silveira,J J Shaw,S M Jeronimo,J M Blackwell

    A genome-wide scan was conducted for visceral leishmaniasis (VL) in Brazil. Initially, 405 markers were typed in 22 multicase pedigrees (28 nuclear families; 174 individuals; 66 affected). Non-parametric multipoint analysis detected nine chromosomal regions with provisional evidence (logarithm of the odds (LOD) scores 0.95-1.66; 0.003

  • Gene expression profiling in a mouse model for African trypanosomiasis.
    Genes. Immun. (IF 2.631) Pub Date : 2006-10-27
    S Kierstein,H Noyes,J Naessens,Y Nakamura,C Pritchard,J Gibson,S Kemp,A Brass

    This study aimed to provide the foundation for an integrative approach to the identification of the mechanisms underlying the response to infection with Trypanosoma congolense, and to identify pathways that have previously been overlooked. We undertook a large-scale gene expression analysis study comparing susceptible A/J and more tolerant C57BL/6 mice. In an initial time course experiment, we monitored the development of parasitaemia and anaemia in every individual. Based on the kinetics of disease progression, we extracted total RNA from liver at days 0, 4, 7, 10 and 17 post infection and performed a microarray analysis. We identified 64 genes that were differentially expressed in the two strains in non-infected animals, of which nine genes remained largely unaffected by the disease. Gene expression profiling at stages of low, peak, clearance and recurrence of parasitaemia suggest that susceptibility is associated with high expression of genes coding for chemokines (e.g. Ccl24, Ccl27 and Cxcl13), complement components (C1q and C3) and interferon receptor alpha (Ifnar1). Additionally, susceptible A/J mice expressed higher levels of some potassium channel genes. In contrast, messenger RNA levels of a few immune response, metabolism and protease genes (e.g. Prss7 and Mmp13) were higher in the tolerant C57BL/6 strain as compared to A/J.

  • A common variant of the interleukin 6 receptor (IL-6r) gene increases IL-6r and IL-6 levels, without other inflammatory effects.
    Genes. Immun. (IF 2.631) Pub Date : 2007-08-03
    S Rafiq,T M Frayling,A Murray,A Hurst,K Stevens,M N Weedon,W Henley,L Ferrucci,S Bandinelli,A-M Corsi,J M Guralnik,D Melzer

    Interleukin-6 (IL-6) is a key inflammatory cytokine, signalling to most tissues by binding to a soluble IL-6 receptor (sIL-6r), making a complex with gp130. We used 1273 subjects (mean age 68 years) from the InCHIANTI Italian cohort to study common variation in the IL-6r locus and associations with interleukin 6 receptor (IL-6r), IL-6, gp130 and a battery of inflammatory markers. The rs4537545 single nucleotide polymorphism (SNP) tags the functional non-synonymous Asp358Ala variant (rs8192284) in IL-6r (r(2)=0.89, n=343). Individuals homozygous for the rs4537545 SNP minor allele (frequency 40%) had a doubling of IL-6r levels (132.48 pg/ml, 95% CI 125.13-140.27) compared to the common allele homozygous group (68.31 pg/ml, 95% CI 65.35-71.41): in per allele regression models, the rs4537545 SNP accounted for 20% of the variance in sIL-6r, with P=5.1 x 10(-62). The minor allele of rs4537545 was also associated with higher circulating IL-6 levels (P=1.9 x 10(-4)). There was no association of this variant with serum levels of gp130 or with any of the studied pro- and anti-inflammatory markers. A common variant of the IL-6r gene results in major changes in IL-6r and IL-6 serum levels, but with no apparent effect on gp130 levels or on inflammatory status in the general population.

  • Human interferon lambda-1 (IFN-lambda1/IL-29) modulates the Th1/Th2 response.
    Genes. Immun. (IF 2.631) Pub Date : 2007-03-16
    W J Jordan,J Eskdale,S Srinivas,V Pekarek,D Kelner,M Rodia,G Gallagher

    Interferon lambda-1 (IFN-lambda1/IL-29) is a member of the Type-III interferon family, which contains three ligands: IFN-lambda1, 2 and 3. These three ligands use the same unique heterodimeric receptor composed of CRF2-12 (IFN-lambda-R1/IL-28Ralpha) and CRF2-4 (IL10-R-beta) chains. Like their close relatives, the Type-I interferons, IFN-lambda1, 2 and 3, promote the phosphorylation of STAT1 and STAT2, induce the ISRE3 complex, elevate OAS and MxA expression and exhibit antiviral activity in vitro. Their use of the IL10-R-beta chain and their ability to phosphorylate STAT3, STAT4 and STAT5 suggested that they may also exhibit immunomodulatory activity; their antiviral action led us to hypothesize that this activity might be directed toward the Th1/Th2 system. Here, we have demonstrated that IFN-lambda1 altered the activity of Th cells in three separate experimental systems: (i) mitogen stimulation, (ii) mixed-lymphocyte reaction (MLR) and (iii) stimulation of naive T cells by monocyte-derived dendritic cells (mDC). In Con-A stimulation assays, the inclusion of IFN-lambda1 consistently led to markedly diminished levels of secreted interleukin (IL-13) with occasional coincident, modest elevation of secreted IFN-gamma. IL-13 secretion was 100-fold more sensitive to IFN-lambda1 than was IFN-gamma secretion. These observations were also made in the allogeneic two-way MLR. IFN-lambda1 was able to alter cytokine-mediated Th biasing and when naive T cells were exposed to allogeneic mDC that had been matured in the presence of IFN-lambda1, secreted IL-13 was again markedly and consistently reduced, whereas secreted IFN-gamma was largely unaltered. These functions were independent of IL-10. Our data support a hitherto unsuspected role for IFN-lambda1 in modulating the development of Th1 and Th2 cells, with an apparent emphasis on the diminution of IL-13 secretion.

  • Interferon lambda-1 (IFN-lambda1/IL-29) induces ELR(-) CXC chemokine mRNA in human peripheral blood mononuclear cells, in an IFN-gamma-independent manner.
    Genes. Immun. (IF 2.631) Pub Date : 2007-01-26
    V Pekarek,S Srinivas,J Eskdale,G Gallagher

    Interferon lambda-1 (IFN-lambda1), the prototype Type-III interferon, has antiviral functions similar to those of the Type-I interferons, IFN-alpha and IFN-beta. However, IFN-lambda1 is capable of signaling through almost all STAT molecules and so it is possible that it may have novel immunoregulatory functions in addition to antiviral ones. From a range of chemokines tested, IFN-lambda1 elevated mRNA levels of only 'Monokine induced by IFN-gamma' (MIG/CXCL9), 'IFN-gamma inducible protein-10' (IP-10/CXCL10) and 'IFN-gamma inducible T-cell alpha chemoattractant' (I-TAC/CXCL11) from human peripheral blood mononuclear cells. As their names suggest, these chemokines are also induced by IFN-gamma, the only member of the Type-II interferon family. This action of IFN-lambda1 did not depend on intermediate induction of IFN-gamma and is therefore, likely to be independent of IFN-gamma. Further, our results suggest that donors responded to IFN-lambda1 stimulation either 'early' or 'late'. Overall the action of IFN-lambda1 was similar to that previously reported for IFN-gamma and may invite more detailed investigation of the role of IFN-lambda1 at the innate/adaptive interface.

  • Modulation of the human cytokine response by interferon lambda-1 (IFN-lambda1/IL-29).
    Genes. Immun. (IF 2.631) Pub Date : 2006-11-04
    W J Jordan,J Eskdale,M Boniotto,M Rodia,D Kellner,G Gallagher

    The interferon lambda family (IFN-lambda1/2/3) is a newly described group of cytokines that are related to both the type-1 interferons and IL-10 family members. These novel cytokines are induced during viral infection and, like type-1 interferons, display significant anti-viral activity. In order to understand their function in more depth, we have examined the ability of IFN-lambda1/IL-29 to regulate cytokine production by human immune cells. Whole peripheral blood mononuclear cells (PBMC) exposed to IFN-lambda1 specifically upregulated IL-6, -8 and -10 but there were no visible effects on TNF or IL-1. This response was produced in a dose-dependant fashion and was inhibited by IL-10. Examination of purified cell populations isolated from PBMC demonstrated that monocytes, rather than lymphocytes, were the major IFN-lambda1-responsive cellular subset, producing IL-6, -8 and -10 in response to IFN-lambda1. Monocyte responses induced by low-level LPS stimulation were also synergistically enhanced by the presence of IFN-lambda1. Human macrophages were also shown to react to IFN-lambda1 similarly to monocytes, by producing the cytokines IL-6, -8 and -10. In conclusion, we have shown that IFN-lambda1, a cytokine produced in response to viral infection, activates both monocytes and macrophages producing a restricted panel of cytokines and may therefore be important in activating innate immune responses at the site of viral infection.

  • DNA microarray allows molecular profiling of rheumatoid arthritis and identification of pathophysiological targets.
    Genes. Immun. (IF 2.631) Pub Date : 2004-10-22
    V Devauchelle,S Marion,N Cagnard,S Mistou,G Falgarone,M Breban,F Letourneur,A Pitaval,O Alibert,C Lucchesi,P Anract,M Hamadouche,X Ayral,M Dougados,X Gidrol,C Fournier,G Chiocchia

    This study was undertaken to evaluate the possibility to obtain a molecular signature of rheumatoid arthritis (RA) comparatively osteoarthritis (OA), and to lay the bases to develop new diagnostic tools and identify new targets. Microarray technology was used for such an analysis. The gene expression profiles of synovial tissues from patients with confirmed RA, and patients with OA were established and compared. A set of 63 genes was selected, based, more specifically, on their overexpression or underexpression in RA samples compared to OA. Results for six of these genes have been verified by quantitative PCR using both samples identical to those used in the microarray experiments and entirely separate samples. Expression profile of the 48 known genes allowed the correct classification of additional RA and OA patients. Furthermore, the distinct expression of three of the selected genes was also studied by quantitative RT-PCR in cultured synovial cells. Detailed analysis of the expression profile of the selected genes provided evidence for dysregulated biological pathways, pointed out to chromosomal location and revealed novel genes potentially involved in RA. It is proposed that such an approach allows valuable diagnosis/prognostics tools in RA to be established and potential targets for combating the disease to be identified.

  • Variants in the gene encoding C3 are associated with asthma and related phenotypes among African Caribbean families.
    Genes. Immun. (IF 2.631) Pub Date : 2005-12-16
    K C Barnes,A V Grant,D Baltadzhieva,S Zhang,T Berg,L Shao,A Zambelli-Weiner,W Anderson,A Nelsen,S Pillai,D P Yarnall,K Dienger,R G Ingersoll,A F Scott,M D Fallin,R A Mathias,T H Beaty,J G N Garcia,M Wills-Karp

    Proinflammatory and immunoregulatory products from C3 play a major role in phagocytosis, respiratory burst, and airways inflammation. C3 is critical in adaptive immunity; studies in mice deficient in C3 demonstrate that features of asthma are significantly attenuated in the absence of C3. To test the hypothesis that the C3 gene on chromosome 19p13.3-p13.2 contains variants associated with asthma and related phenotypes, we genotyped 25 single nucleotide polymorphism (SNP) markers distributed at intervals of approximately 1.9 kb within the C3 gene in 852 African Caribbean subjects from 125 nuclear and extended pedigrees. We used the multiallelic test in the family-based association test program to examine sliding windows comprised of 2-6 SNPs. A five-SNP window between markers rs10402876 and rs366510 provided strongest evidence for linkage in the presence of linkage disequilibrium for asthma, high log[total IgE], and high log[IL-13]/[log[IFN-gamma] in terms of global P-values (P = 0.00027, 0.00013, and 0.003, respectively). A three-SNP haplotype GGC for the first three of these markers showed best overall significance for the three phenotypes (P = 0.003, 0.007, 0.018, respectively) considering haplotype-specific tests. Taken together, these results implicate the C3 gene as a priority candidate controlling risk for asthma and allergic disease in this population of African descent.

  • Genetic risk factors for infection in patients with early rheumatoid arthritis.
    Genes. Immun. (IF 2.631) Pub Date : 2004-11-05
    L B Hughes,L A Criswell,T M Beasley,J C Edberg,R P Kimberly,L W Moreland,M F Seldin,S L Bridges

    We analyzed clinical and genetic factors contributing to infections in 457 subjects with early rheumatoid arthritis (RA) enrolled in a prospective, 1-year clinical trial of methotrexate and the TNF inhibitor etanercept. Subjects were genotyped for the following single nucleotide polymorphisms (SNPs): (TNF -308, -238, and + 488); lymphotoxin-alpha (LTA) (LTA + 249, + 365, and + 720); and Fc gamma receptors FCGR2A 131 H/R; FCGR3A 176 F/V; and FCGR3B NA 1/2 and genotypes were correlated with infections. At least one URI was noted in 52% of subjects (99/191) with the NA2/NA2 genotype of the neutrophil-specific FCGR3B gene, compared to 42% (77/181) of those with the NA1/NA2 genotype and 39% (23/59) of those with the NA1/NA1 genotype (P = 0.038). Urinary tract infection (UTI) was associated with the TNF -238 A (odds ratio(OR) 2.56, 95% confidence interval (CI) 1.05-6.25) and LTA +365 C (OR 1.73, 95% CI 1.07-2.79) alleles, and marginally with the FCGR3A F allele (OR 1.72, 95% CI 0.99-3.00). There was a striking linear correlation between UTI and the number of risk alleles defined by these three SNPs (P < 0.001), suggesting an additive effect on susceptibility. These findings have important implications for the role of genetics in susceptibility to bacterial and viral infections.

  • Novel mutations in a Japanese patient with CD19 deficiency.
    Genes. Immun. (IF 2.631) Pub Date : 2007-09-21
    H Kanegane,K Agematsu,T Futatani,M M Sira,K Suga,T Sekiguchi,M C van Zelm,T Miyawaki

    Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by recurrent bacterial infections, hypogammaglobulinemia and low to normal numbers of circulating B cells. Mutations in the ICOS, TACI and CD19 genes have recently been identified in <10% of CVID patients. We, herein, describe two novel CD19 gene disruptions in an 8-year-old Japanese boy, who had been clinically diagnosed as having CVID at the age of 5 years. Flow-cytometric analysis demonstrated absence of CD19 and reduced CD21 expression on CD20-postive peripheral blood B cells. Mutation analysis of CD19 revealed a mutation in the splice acceptor site of intron 5 (IVS5-1G>T) of the maternal allele, resulting in skipping of exon 6, and a truncated protein product. The paternal allele was disrupted by a gross deletion encompassing at least the ATP2A1, CD19 and NFATC2IP genes. The patient had a small number of IgD(-) CD27(+) memory B cells, in which somatic mutation were detected. His B cells showed substantial proliferation upon stimulation, but reduced IgG and IgA production in vitro. These findings extend the mutation spectrum of the CD19 deficiency to four, and confirm the homogeneity of the CD19 deficiency as a unique type of CVID.

  • Polymorphic variation in the CBLB gene in human type 1 diabetes.
    Genes. Immun. (IF 2.631) Pub Date : 2004-02-13
    R Kosoy,N Yokoi,S Seino,P Concannon

    CBLB was evaluated as a candidate gene for type 1 diabetes (T1D) susceptibility based on its association with autoimmunity in animal models and its role in T-cell costimulatory signaling. Cblb is one of the two major diabetes predisposing loci in the Komeda diabetes-prone (KDP) rat. Cbl-b, a ubiquitin ligase, couples TCR-mediated stimulation with the requirement for CD28 costimulation, regulating T-cell activation. To identify variants with possible effects on gene function as well as haplotype tagging polymorphisms, the human CBLB coding region was sequenced in 16 individuals with T1D: no variants predicted to change the amino-acid sequence were identified. Seven single-nucleotide polymorphism (SNP) markers spanning the CBLB gene were genotyped in multiplex T1D families and assessed for disease association by transmission disequilibrium testing. No significant evidence of association was obtained for either individual markers or marker haplotypes.

  • Spontaneous mutations in the mouse Sharpin gene result in multiorgan inflammation, immune system dysregulation and dermatitis.
    Genes. Immun. (IF 2.631) Pub Date : 2007-06-01
    R E Seymour,M G Hasham,G A Cox,L D Shultz,H Hogenesch,D C Roopenian,J P Sundberg

    Homologues of the SHARPIN (SHANK-associated RH domain-interacting protein) gene have been identified in the human, rat and mouse genomes. SHARPIN and its homologues are expressed in many tissues. SHARPIN protein forms homodimers and associates with SHANK in the post-synaptic density of excitatory neurotransmitters in the brain. SHARPIN is hypothesized to have roles in the crosslinking of SHANK proteins and in enteric nervous system function. We demonstrate that two independently arising spontaneous mutations in the mouse Sharpin gene, cpdm and cpdm(Dem), cause a chronic proliferative dermatitis phenotype, which is characterized histologically by severe inflammation, eosinophilic dermatitis and defects in secondary lymphoid organ development. These are the first examples of disease-causing mutations in the Sharpin gene and demonstrate the importance of SHARPIN protein in normal immune development and control of inflammation.

  • Identification, characterization, and evolution of a primate beta-defensin gene cluster.
    Genes. Immun. (IF 2.631) Pub Date : 2005-03-18
    Y Radhakrishnan,K G Hamil,S Yenugu,S L Young,F S French,S H Hall

    Defensins are members of a large diverse family of cationic antimicrobial peptides that share a signature pattern consisting of six conserved cysteine residues. Defensins have a wide variety of functions and their disruption has been implicated in various human diseases. Here we report the characterization of DEFB119-DEFB123, five genes in the human beta-defensin cluster locus on chromosome 20q11.1. The genomic structures of DEFB121 and DEFB122 were determined in silico. Sequences of the five macaque orthologs were obtained and expression patterns of the genes were analyzed in humans and macaque by semiquantitative reverse transcription polymerase chain reaction. Expression was restricted to the male reproductive tract. The genes in this cluster are differentially regulated by androgens. Evolutionary analyses suggest that this cluster originated by a series of duplication events and by positive selection. The evolutionary forces driving the proliferation and diversification of these defensins may be related to reproductive specialization and/or the host-parasite coevolutionary process.

  • Interleukin-20 promotes angiogenesis in a direct and indirect manner.
    Genes. Immun. (IF 2.631) Pub Date : 2006-03-03
    M-Y Hsieh,W-Y Chen,M-J Jiang,B-C Cheng,T-Y Huang,M-S Chang

    IL-20 belongs to the IL-10 family and is involved in the pathogenesis of keratinocyte hyperproliferation in vivo. Endothelial cells express IL-20 receptors. To explore the function of IL-20 on endothelial cells, we treated human umbilical vein endothelial cells (HUVECs) and human microvascular endothelial cells (HMECs) with human IL-20 and analyzed its effect on endothelial cells. IL-20 induced proliferation of endothelial cells and the activity was specifically blocked by anti-human-IL-20 monoclonal antibody and soluble (s)IL-20 receptor (R)1 and sIL-20R2. An alternatively spliced variant of IL-20 was isolated and also was shown to induce proliferation of HUVECs and HMECs. Treatment of HUVECs with both IL-10 and IL-20 demonstrated that IL-10 antagonized the activity of IL-20 because it diminished IL-20-induced proliferation of HUVECs. IL-20 significantly induced HUVECs migration and vascular tube formation on Matrigel in vitro. In vivo, IL-20 also enhanced tumor angiogenesis. Incubation of IL-20 with HUVECs induced transcripts of bFGF, VEGF, MMP-2, MMP-9, and IL-8. Furthermore, incubation of HUVECs with IL-20 induced phosphorylation of ERK1/2, p38, and JNK. Thus, IL-20 is a pleiotropic cytokine and promotes angiogenesis.

  • Possible relations between the polymorphisms of the cytokines IL-19, IL-20 and IL-24 and plaque-type psoriasis.
    Genes. Immun. (IF 2.631) Pub Date : 2005-05-13
    S Kõks,K Kingo,K Vabrit,R Rätsep,M Karelson,H Silm,E Vasar

    The aim of present study was to elucidate the role of the interleukin (IL)-24 gene in predicting risk for plaque-type psoriasis and to describe the linkage disequilibrium (LD) pattern emerging from the genes of IL-19, IL-20 and IL-24. Genes encoding IL-19, IL-20 and IL-24 locate in the region q32 of chromosome 1. The association between the single-nucleotide polymorphisms (SNPs) or haplotypes of the IL-24 gene and the susceptibility of psoriasis was not found. However, a significant protective effect of the combined haplotype CAAAC of IL-20 and IL-24 genes against plaque-type psoriasis was established (OR 0.154). Protective effect against psoriasis was also observed with haplotype TGGGT (OR 0.591) and haplotype CGAGT (OR 0.457). Performing a comprehensive analysis using the data regarding SNPs of IL-24 gene together with the previously published data regarding IL-19 and IL-20 SNPs, we identified two haplotype blocks within the region q32 of chromosome 1. The main result of the present study is that while the IL-19/IL-20 extended haplotype CACCGGAA is a significant susceptibility factor for psoriasis (previous study), IL-20/IL-24 haplotypes CAAAC, TGGGT and CGAGT have a significant protective effect. Nevertheless, family-based studies are required to confirm the impact of IL-19, IL-20 and IL-24 genes in the genetic predisposition for psoriasis.

  • Combined haplotype analysis of the interleukin-19 and -20 genes: relationship to plaque-type psoriasis.
    Genes. Immun. (IF 2.631) Pub Date : 2004-10-22
    S Kõks,K Kingo,R Rätsep,M Karelson,H Silm,E Vasar

    There is increasing evidence to suggest that the newly discovered cytokines interleukin (IL)-19 and -20 have a role in the function of epidermis and in psoriasis. The genes encoding these cytokines locate into the genomic IL-10 region on human chromosome 1. The aim of the present study was to analyze whether single-nucleotide polymorphisms (SNPs) in these genes have an impact on the susceptibility for psoriasis. From pairwise linkage disequilibrium (LD) matrix of the IL-19 and -20 gene polymorphisms, what reflects the nonrandom association of alleles at these markers, it was apparent that IL-19 and -20 genes form one block of LD. We found that the HT3 CACCGGAA haplotype of the IL-19 and -20 genes was associated with an increased risk of psoriasis, reflecting its role in determining susceptibility to plaque-type psoriasis. Although association analysis of the IL-19 gene indicated that minor alleles of the IL-19 gene SNPs (rs2243188, rs2243169 and rs2243158) revealed protective effect to psoriasis and haplotype analysis of the IL-19 gene proved significant protective effect of the TGATA haplotype in case of late-onset disease, combined haplotype analysis of the IL-19 and -20 genes demonstrated that protective effect of the IL-19 gene is secondary to the susceptibility effect of the IL-20 gene.

  • Polymorphisms in the interleukin-20 gene: relationships to plaque-type psoriasis.
    Genes. Immun. (IF 2.631) Pub Date : 2004-01-09
    K Kingo,S Kõks,T Nikopensius,H Silm,E Vasar

    We analyzed the frequency of single-nucleotide polymorphisms (SNPs) at positions -1053 (rs 2981572), 1380 (rs 2981573), 1462 (rs 2232360), and 3978 (rs 1518108) of the human interleukin-20 (IL-20) gene by tetraprimer ARMS-PCR method. A significant association between patients with psoriasis and the G allele at position -1053 (P<0.05) was established. The pairwise linkage disequilibrium (LD) matrix showed that the nearly complete LD was present within the polymorphisms at positions -1053, 1380, and 1462 of the IL-20 gene. We found that patients with plaque psoriasis had a higher frequency of the HT3 GAA haplotype (P<0.01, OR 2.341, 95% CI: 1.346-4.074) compared to the control group. Likewise, the HT3 GAA haplotype was associated with an increased risk of early-onset psoriasis (P<0.01, OR 2.305, 95% CI: 1.285-4.132), late onset of disease (P<0.01, OR 2.542, 95% CI: 1.266-5.102), familial psoriasis (P<0.02, OR 2.220, 95% CI: 1.249-3.945), and sporadic disease (P<0.01, OR 2.523, 95% CI: 1.390-4.580). Our data indicate that IL-20 gene polymorphisms should have a role in determining susceptibility to plaque-type psoriasis. The possible role of the studied SNPs in the regulation of the expression of IL-20 is unknown yet and needs further studies.

  • Association of interleukin-10 promoter polymorphisms with systemic lupus erythematosus.
    Genes. Immun. (IF 2.631) Pub Date : 2004-08-06
    W P Chong,W K Ip,W H-S Wong,C S Lau,T M Chan,Y L Lau

    Several lines of evidence suggest interleukin-10 gene (IL-10) is a candidate gene in susceptibility to systemic lupus erythematosus (SLE). We investigated the association of IL-10 promoter single-nucleotide polymorphisms (SNPs) (-3575T/A, -2849G/A, -2763C/A, -1082A/G, -819T/C and -592A/C) and microsatellites (IL10.R, IL10.G) with SLE in 554 Hong Kong Chinese patients and 708 ethnically matched controls. Six haplotypes (hts) were identified from the SNPs. The genotype distribution of the ht1 (T-C-A-T-A), which is associated with low IL-10 production, was different in patients and controls (P=0.009). The homozygous genotype of non-ht1 was significantly increased in patients (P=0.009, odds ratio (OR)=1.80, 95% CI: 1.15-2.82). The frequency of IL10.G4 of IL10.G was also significantly increased in patients (P=0.017, OR=2.53, 95% CI: 1.18-5.40). We found that the homozygous non-ht1 combined with short allele (CA repeat number < or =21) of IL10.G has a dose-dependent effect on SLE susceptibility: non-ht1/non-ht1 with homozygous short allele showed a higher OR (OR=4.11, 95% CI: 1.27-13.2, P=0.018) of association with SLE than the genotype of non-ht1/non-ht1 with heterozygous short/long allele (OR=2.98, 95% CI: 1.26-7.07, P=0.013) and homozygous long allele (OR=1.05, 95% CI: 0.62-1.78, P=0.848). The frequency of non-ht1 was significantly increased in patients with serositis (P<0.0001, OR=2.42, 95% CI: 1.55-3.80). In conclusion, the high expression promoter genotype is associated with SLE in Chinese.

Contents have been reproduced by permission of the publishers.