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Genes and Immunity

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.
July 9, 2018: Genes and Immunity
Kate F Kernan, Lina Ghaloul-Gonzalez, Bita Shakoory, John A Kellum, Derek C Angus, Joseph A Carcillo
Post-hoc subgroup analysis of the negative trial of interleukin-1β receptor antagonist (IL1RA) for septic shock suggested that patients with features of macrophage activation syndrome (MAS) experienced a 50% relative risk reduction for mortality with treatment. Here we seek a genetic basis for this differential response. From 1341 patients enrolled in the ProCESS trial of early goal directed therapy for septic shock, we selected 6 patients with MAS features and the highest ferritin, for whole exome sequencing (mean 24,030...
July 6, 2018: Genes and Immunity
Michelle M Stein, Cara L Hrusch, Anne I Sperling, Carole Ober
The low affinity Fcγ receptor, FcγRIIA, harbors a common missense mutation, rs1801274 (G>A, Arg131His) that modifies binding affinity to human IgG2 and mouse IgG1 antibodies and is associated with increased risk of autoimmune disease. Despite the important role of the Arg131His variant, little is understood about heterozygous genotype effects on global gene expression and cytokine production during an FcγR-dependent response. To address this gap in knowledge, we treated human whole-blood samples from 130 individuals with mouse IgG1 anti-CD3 and anti-CD28 antibodies and characterized the genome-wide gene expression profiles and cytokine production among individuals stratified by rs1801274 genotype...
July 6, 2018: Genes and Immunity
Yan Teng, Mingqi Luo, Ting Yu, Lang Chen, Qiuling Huang, Shuliang Chen, Linlin Xie, Yan Zeng, Fan Luo, Hairong Xiong, Yuanyuan Liu, Wei Hou, Yong Feng
The human immunodeficiency virus type 1 (HIV-1) causes persistent infection in human and induces miR-146a expression in infected cells. miR-146a represses the innate immune response by inhibiting the expression of TRAF6 and IRAK1 genes, thus negatively controls the NF-κB-related cytokines and interferon stimulated genes. Here we reported that lentiviral CRISPR/Cas9 system was highly efficient in introducing mutations in the precursor miR-146a genomic sequences, resulting in a loss of miR-146a expression and function...
July 2, 2018: Genes and Immunity
Peter S Linsley, Carla J Greenbaum, Mario Rosasco, Scott Presnell, Kevan C Herold, Matthew J Dufort
Biologic treatment of type 1 diabetes (T1D) with agents including anti-CD3 (otelixizumab and teplizumab), anti-CD20 (rituximab), LFA3Ig (alafacept), and CTLA4Ig (abatacept) results in transient stabilization of insulin C-peptide, a surrogate for endogenous insulin secretion. With the goal of inducing more robust immune tolerance, we used systems biology approaches to elucidate mechanisms associated with C-peptide stabilization in clinical trial blood samples from new-onset T1D subjects treated with the B cell-depleting drug, rituximab...
June 21, 2018: Genes and Immunity
Jing Xu, Yan Shang, Feng Cai, Shu Zhang, Zhong Xiao, Haitao Wang, Yanhong Fan, Ting Li, Shuhong Sheng, Youhui Fu, Feng Chi, Chen Zhou
To further investigate the relationship between lung cancer and hedgehog interacting protein (HHIP) polymorphisms of chronic obstructive pulmonary disease (COPD) patients, we conducted a case-control study in a Chinese Han population. Six HHIP SNPs with minor allele frequencies >5% (rs1489758, rs1489759, rs10519717, rs13131837, rs1492820, and rs7689420) were analyzed in 1,017 COPD patients (767 males and 246 females) and 430 non-COPD patients. Using logistic regression analysis, we found that rs7689420 was significantly associated with lung cancer in COPD patients in the Chinese Han population (P < 0...
June 19, 2018: Genes and Immunity
Steven J Mack, Julia Udell, Franziska Cohen, Kazutoyo Osoegawa, Sharon K Hawbecker, David A Noonan, Martha B Ladner, Damian Goodridge, Elizabeth A Trachtenberg, Jorge R Oksenberg, Henry A Erlich
Since the publication of this article, the authors have found that the numbers of patients and controls were reversed. This study included 412 MS patients and 419 controls. This correction applies to the Abstract, the final paragraph of the Introduction, and the first paragraph of the Materials and Methods. This was entirely a reporting error and does not impact the Results or Conclusions.
June 18, 2018: Genes and Immunity
Nicolas De Neuter, Esther Bartholomeus, George Elias, Nina Keersmaekers, Arvid Suls, Hilde Jansens, Evelien Smits, Niel Hens, Philippe Beutels, Pierre Van Damme, Geert Mortier, Viggo Van Tendeloo, Kris Laukens, Pieter Meysman, Benson Ogunjimi
Pathogens of past and current infections have been identified directly by means of PCR or indirectly by measuring a specific immune response (e.g., antibody titration). Using a novel approach, Emerson and colleagues showed that the cytomegalovirus serostatus can also be accurately determined by using a T cell receptor repertoire data mining approach. In this study, we have sequenced the CD4+ memory T cell receptor repertoire of a Belgian cohort with known cytomegalovirus serostatus. A random forest classifier was trained on the CMV specific T cell receptor repertoire signature and used to classify individuals in the Belgian cohort...
June 15, 2018: Genes and Immunity
Leah C Kottyan, Avery Maddox, Julian R Braxton, Emily M Stucke, Vince Mukkada, Philip E Putnam, J Pablo Abonia, Mirna Chehade, Robert A Wood, Robbie D Pesek, Brian P Vickery, Glenn T Furuta, Peter Dawson, Hugh A Sampson, Lisa J Martin, Jennifer A Kelly, Robert P Kimberly, Kathy Sivils, Patrick M Gaffney, Kenneth Kaufman, John B Harley, Marc E Rothenberg
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus triggered by immune hypersensitivity to food. Herein, we tested whether genetic risk factors for known, non-allergic, immune-mediated diseases, particularly those involving autoimmunity, were associated with EoE risk. We used the high-density Immunochip platform, encoding 200,000 genetic variants for major auto-immune disease. Accordingly, 1214 subjects with EoE of European ancestry and 3734 population controls were genotyped and assessed using data directly generated or imputed from the previously published GWAS...
June 8, 2018: Genes and Immunity
Victoria L DeVault, Murisa Malagic, Linda Mei, Oliver Dienz, Graham W J Lilley, Patrick Benoit, Somen K Mistri, Shawn C Musial, Jennifer L Ather, Matthew E Poynter, Jonathan E Boyson
Invariant NKT (iNKT) cells are tissue-resident innate-like T cells critical to the host immune response. We previously identified a 6.6 Mbp region on chromosome 1 as a major regulator of iNKT cell number and function in C57BL/6 and 129X1/SvJ mice. Here, we fine-mapped this locus by assessing the iNKT cell response to alpha-galactosylceramide (αGalCer) in a series of B6.129 congenic lines. This analysis revealed the presence of at least two genetic elements that regulate iNKT cell cytokine production in response to αGalCer...
June 8, 2018: Genes and Immunity
Ning Li, Fan Luo, Qingzhou Chen, Ni Zhu, Hui Wang, Linlin Xie, Hairong Xiong, Ming Yue, Yun Zhang, Yong Feng, Wei Hou
Hantaan virus (HTNV), member of the newly defined Hantaviridae family, within the order Bunyavirales, can cause a hemorrhagic fever with renal syndrome with high fatality rates in humans. However, no specific antiviral agents are currently available for HTNV infection approved by the US Food and Drug Administration. Although interferon lambdas (IFN-λs) have been shown to induce an antiviral state against HTNV, the molecular mechanisms remain to be determined. In this study, we found that IFN-λs exerted its anti-HTNV effect by activating Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway-mediated antiviral immunity in A549 cells...
May 15, 2018: Genes and Immunity
Mumtaz Y Balkhi, Jami Willette-Brown, Gabor Wittmann, Yinling Hu
Only few genes have been confidently identified to be involved in the Follicular (FO) and Marginal Zone (MZ) B cell differentiation, migration, and retention in the periphery. Our group previously observed that IKKα kinase inactive mutant mice IKKα K44A/K44A have significantly lower number of MZ B cells whereas FO B cell numbers appeared relatively normal. Because kinase dead IKKα can retain some of its biological functions that may interfere in revealing its actual role in the MZ and FO B cell differentiation...
May 8, 2018: Genes and Immunity
Seema Patel, Lei Jin
TMEM173 gene encodes the protein STING (stimulator of interferon genes), a key player in host defense against pathogens. Mutations in the human TMEM173 gene cause a life-threatening auto-inflammatory disease called SAVI (STING-associated vasculopathy with onset in infancy). Human STING is also a promising therapeutic target for cancers and infectious diseases. Recently, Aduro Biotech and Novartis announced a $250M-plus initiative to develop STING-targeting cancer immunotherapies. Thus, understanding the genetics of the human TMEM173 gene is important for both basic and translational research...
May 1, 2018: Genes and Immunity
Madalina E Carter-Timofte, Anders F Hansen, Mette Christiansen, Søren R Paludan, Trine H Mogensen
Recently, deficiency in the cytosolic DNA sensor RNA Polymerase III was described in children with severe primary varicella-zoster virus (VZV) infection in the CNS and lungs. In the present study we examined adult patients with VZV CNS infection caused by viral reactivation. By whole exome sequencing we identified mutations in POL III genes in two of eight patients. These mutations were located in the coding regions of the subunits POLR3A and POLR3E. In functional assays, we found impaired expression of antiviral and inflammatory cytokines in response to the POL III agonist Poly(dA:dT) as well as increased viral replication in patient cells compared to controls...
May 1, 2018: Genes and Immunity
Bijun Wen, Tomas Tokar, Amel Taibi, Jianmin Chen, Igor Jurisica, Elena M Comelli
Citrobacter rodentium is a murine pathogen causing transmissible colonic hyperplasia and colitis with a pathogenic mechanism similar to foodborne enterohaemorrhagic Escherichia coli in humans. Mechanisms underlying intestinal responses to C. rodentium infection are incompletely understood. We identified 24 colonic microRNAs (miRNAs) as significantly deregulated in response to C. rodentium, including miR-7a, -17, -19a, -20a, -20b, -92a, -106a, -132, -200a, and -2137; most of these miRNAs belong to the oncogenic miR-17-92 clusters...
May 1, 2018: Genes and Immunity
Roozbeh Sanaei, Nima Rezaei, Asghar Aghamohammadi, Ali-Akbar Delbandi, Shahram Teimourian, Reza Yazdani, Parsova Tavasolian, Fatemeh Kiaee, Nader Tajik
Common variable immunodeficiency (CVID), a clinically symptomatic primary immunodeficiency disease (PID), is characterized by hypogammaglobulinemia leading to recurrent infections and various complications. Recently, some defects in the signaling of TLRs have been identified in CVID patients which led us to investigate the expression of TLR4 and 9 negative regulatory molecules and their upregulation status following their activation. Using TaqMan real-time PCR, SOCS1, TNFAIP3, RFN216, and IRAK-M transcripts among peripheral blood mononuclear cells (PBMCs) were measured with/without TLR4 and 9 activations...
April 5, 2018: Genes and Immunity
Allison E Reeme, Tiffany A Claeys, Praful Aggarwal, Amy J Turner, John M Routes, Ulrich Broeckel, Richard T Robinson
Human IL12RB1 is an autosomal gene that is essential for mycobacterial disease resistance and T cell differentiation. Using primary human tissue and PBMCs, we demonstrate that lung and T cell IL12RB1 expression is allele-biased, and the extent to which cells express one IL12RB1 allele is unaffected by activation. Furthermore following its expression the IL12RB1 pre-mRNA is processed into either IL12RB1 Isoform 1 (IL12Rβ1, a positive regulator of IL12 responsiveness) or IL12RB1 Isoform 2 (a protein of heretofore unknown function)...
March 30, 2018: Genes and Immunity
Michael C Campbell, Lunden T Smith, Jayla Harvey
Despite its critical role in the defense against microbial infection and tumor development, little is known about the range of nucleotide and haplotype variation at IFN-γ, or the evolutionary forces that have shaped patterns of diversity at this locus. To address this gap in knowledge, we examined sequence data from the IFN-γ gene in 1461 individuals from 15 worldwide populations. Our analyses uncovered novel patterns of variation in distinct African populations, including an excess of high frequency-derived alleles, unusually long haplotype structure surrounding the IFN-γ gene, and a "star-like" genealogy of African-specific haplotypes carrying variants previously associated with infectious disease...
March 29, 2018: Genes and Immunity
Kelly A Shaw, David J Cutler, David Okou, Anne Dodd, Bruce J Aronow, Yael Haberman, Christine Stevens, Thomas D Walters, Anne Griffiths, Robert N Baldassano, Joshua D Noe, Jeffrey S Hyams, Wallace V Crandall, Barbara S Kirschner, Melvin B Heyman, Scott Snapper, Stephen Guthery, Marla C Dubinsky, Jason M Shapiro, Anthony R Otley, Mark Daly, Lee A Denson, Subra Kugathasan, Michael E Zwick
In the United States, approximately 5% of individuals with inflammatory bowel disease (IBD) are younger than 20 years old. Studies of pediatric cohorts can provide unique insights into genetic architecture of IBD, which includes Crohn's disease (CD) and ulcerative colitis (UC). Large genome-wide association studies have found more than 200 IBD-associated loci but explain a minority of disease variance for CD and UC. We sought to characterize the contribution of rare variants to disease development, comparing exome sequencing of 368 pediatric IBD patients to publicly available exome sequencing (dbGaP) and aggregate frequency data (ExAC)...
March 28, 2018: Genes and Immunity
Matthew L Stoll, M Kathy Pierce, Jordan A Watkins, Mingce Zhang, Pamela F Weiss, Jennifer E Weiss, Charles O Elson, Randy Q Cron, Ranjit Kumar, Casey D Morrow, Trenton R Schoeb
Studies have identified abnormalities in the microbiota of patients with arthritis. To evaluate the pathogenicity of human microbiota, we performed fecal microbial transplantation from children with spondyloarthritis and controls to germ-free KRN/B6xNOD mice. Ankle swelling was equivalent in those that received patient vs. control microbiota. Principal coordinates analysis revealed incomplete uptake of the human microbiota with over-representation of two genera (Bacteroides and Akkermansia) among the transplanted mice...
March 24, 2018: Genes and Immunity
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