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Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy.
Johnson DB, Estrada MV, Salgado R, Sanchez V, Doxie DB, Opalenik SR, Vilgelm AE, Feld E, Johnson AS, Greenplate AR, Sanders ME, Lovly CM, Frederick DT, Kelley MC, Richmond A, Irish JM, Shyr Y, Sullivan RJ, Puzanov I, Sosman JA, Balko JM
(2016) Nat Commun 7: 10582
MeSH Terms: Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Cell Line, Tumor, Gene Expression Regulation, Neoplastic, Genes, MHC Class II, Genotype, Humans, Melanoma, Nivolumab, Programmed Cell Death 1 Receptor, RNA, Messenger
Show Abstract · Added January 30, 2016
Anti-PD-1 therapy yields objective clinical responses in 30-40% of advanced melanoma patients. Since most patients do not respond, predictive biomarkers to guide treatment selection are needed. We hypothesize that MHC-I/II expression is required for tumour antigen presentation and may predict anti-PD-1 therapy response. In this study, across 60 melanoma cell lines, we find bimodal expression patterns of MHC-II, while MHC-I expression was ubiquitous. A unique subset of melanomas are capable of expressing MHC-II under basal or IFN╬│-stimulated conditions. Using pathway analysis, we show that MHC-II(+) cell lines demonstrate signatures of 'PD-1 signalling', 'allograft rejection' and 'T-cell receptor signalling', among others. In two independent cohorts of anti-PD-1-treated melanoma patients, MHC-II positivity on tumour cells is associated with therapeutic response, progression-free and overall survival, as well as CD4(+) and CD8(+) tumour infiltrate. MHC-II(+) tumours can be identified by melanoma-specific immunohistochemistry using commercially available antibodies for HLA-DR to improve anti-PD-1 patient selection.
4 Communities
6 Members
0 Resources
11 MeSH Terms
Mapping the genetic architecture of gene expression in human liver.
Schadt EE, Molony C, Chudin E, Hao K, Yang X, Lum PY, Kasarskis A, Zhang B, Wang S, Suver C, Zhu J, Millstein J, Sieberts S, Lamb J, GuhaThakurta D, Derry J, Storey JD, Avila-Campillo I, Kruger MJ, Johnson JM, Rohl CA, van Nas A, Mehrabian M, Drake TA, Lusis AJ, Smith RC, Guengerich FP, Strom SC, Schuetz E, Rushmore TH, Ulrich R
(2008) PLoS Biol 6: e107
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Animals, Child, Child, Preschool, Cholesterol, LDL, Coronary Artery Disease, Diabetes Mellitus, Type 1, Female, Gene Expression Profiling, Genes, MHC Class II, Genetic Predisposition to Disease, Genome, Human, Genotype, Humans, Infant, Liver, Male, Mice, Middle Aged, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Quantitative Trait Loci, RNA, Messenger, Transcription, Genetic
Show Abstract · Added March 26, 2014
Genetic variants that are associated with common human diseases do not lead directly to disease, but instead act on intermediate, molecular phenotypes that in turn induce changes in higher-order disease traits. Therefore, identifying the molecular phenotypes that vary in response to changes in DNA and that also associate with changes in disease traits has the potential to provide the functional information required to not only identify and validate the susceptibility genes that are directly affected by changes in DNA, but also to understand the molecular networks in which such genes operate and how changes in these networks lead to changes in disease traits. Toward that end, we profiled more than 39,000 transcripts and we genotyped 782,476 unique single nucleotide polymorphisms (SNPs) in more than 400 human liver samples to characterize the genetic architecture of gene expression in the human liver, a metabolically active tissue that is important in a number of common human diseases, including obesity, diabetes, and atherosclerosis. This genome-wide association study of gene expression resulted in the detection of more than 6,000 associations between SNP genotypes and liver gene expression traits, where many of the corresponding genes identified have already been implicated in a number of human diseases. The utility of these data for elucidating the causes of common human diseases is demonstrated by integrating them with genotypic and expression data from other human and mouse populations. This provides much-needed functional support for the candidate susceptibility genes being identified at a growing number of genetic loci that have been identified as key drivers of disease from genome-wide association studies of disease. By using an integrative genomics approach, we highlight how the gene RPS26 and not ERBB3 is supported by our data as the most likely susceptibility gene for a novel type 1 diabetes locus recently identified in a large-scale, genome-wide association study. We also identify SORT1 and CELSR2 as candidate susceptibility genes for a locus recently associated with coronary artery disease and plasma low-density lipoprotein cholesterol levels in the process.
0 Communities
1 Members
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27 MeSH Terms
Natural killer T cells and CD8+ T cells are dispensable for T cell-dependent allergic airway inflammation.
Das J, Eynott P, Jupp R, Bothwell A, Van Kaer L, Shi Y, Das G
(2006) Nat Med 12: 1345-6; author reply 1347
MeSH Terms: Animals, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Genes, MHC Class II, Inflammation, Killer Cells, Natural, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Respiratory Hypersensitivity, Respiratory Tract Diseases, T-Lymphocytes
Added December 10, 2013
0 Communities
1 Members
0 Resources
13 MeSH Terms
Coordinated changes of histone modifications and HDAC mobilization regulate the induction of MHC class II genes by Trichostatin A.
Gialitakis M, Kretsovali A, Spilianakis C, Kravariti L, Mages J, Hoffmann R, Hatzopoulos AK, Papamatheakis J
(2006) Nucleic Acids Res 34: 765-72
MeSH Terms: Acetylation, Antineoplastic Agents, Cell Line, Tumor, Chromatin Immunoprecipitation, DNA-Binding Proteins, Enhancer Elements, Genetic, Enzyme Inhibitors, Gene Expression Profiling, Genes, MHC Class II, HLA-DR Antigens, HLA-DR alpha-Chains, HeLa Cells, Histone Deacetylase Inhibitors, Histones, Humans, Hydroxamic Acids, Regulatory Factor X Transcription Factors, Transcription Factors, Transcriptional Activation
Show Abstract · Added November 18, 2010
The deacetylase inhibitor Trichostatin A (TSA) induces the transcription of the Major Histocompatibility Class II (MHC II) DRA gene in a way independent of the master coactivator CIITA. To analyze the molecular mechanisms by which this epigenetic regulator stimulates MHC II expression, we used chromatin immunoprecipitation (ChIP) assays to monitor the alterations in histone modifications that correlate with DRA transcription after TSA treatment. We found that a dramatic increase in promoter linked histone acetylation is followed by an increase in Histone H3 lysine 4 methylation and a decrease of lysine 9 methylation. Fluorescence recovery after photobleaching (FRAP) experiments showed that TSA increases the mobility of HDAC while decreasing the mobility of the class II enhanceosome factor RFX5. These data, in combination with ChIP experiments, indicate that the TSA-mediated induction of DRA transcription involves HDAC relocation and enhanceosome stabilization. In order to gain a genome-wide view of the genes responding to inhibition of deacetylases, we compared the transcriptome of B cells before and after TSA treatment using Affymetrix microarrays. This analysis showed that in addition to the DRA gene, the entire MHC II family and the adjacent histone cluster that are located in chromosome 6p21-22 locus are strongly induced by TSA. A complex pattern of gene reprogramming by TSA involves immune recognition, antiviral, apoptotic and inflammatory pathways and extends the rationale for using Histone Deacetylase Inhibitors (HDACi) to modulate the immune response.
1 Communities
1 Members
0 Resources
19 MeSH Terms
Host genetic profiles predict virological and immunological control of HIV-1 infection in adolescents.
Tang J, Wilson CM, Meleth S, Myracle A, Lobashevsky E, Mulligan MJ, Douglas SD, Korber B, Vermund SH, Kaslow RA, REACH Study Group. Reaching for Excellence in Adolescent Care and Health
(2002) AIDS 16: 2275-84
MeSH Terms: Adolescent, Algorithms, Alleles, CD4 Lymphocyte Count, Female, Follow-Up Studies, Genes, MHC Class II, Genetic Markers, Genetic Predisposition to Disease, HIV Infections, HIV-1, Haplotypes, Histocompatibility Testing, Humans, Male, Prognosis, Receptors, CCR2, Receptors, Chemokine, Viral Load, Viremia
Show Abstract · Added March 5, 2014
OBJECTIVE - To evaluate the correlation between host genetic profiles and virological and immunological outcomes among HIV-1-seropositive participants from the Reaching for Excellence in Adolescent Care and Health (REACH) cohort.
METHODS - HLA class I and chemokine coreceptor (CCR) alleles and haplotypes were resolved in 227 HIV-1-seropositive adolescents (ages 13-18 years; 75% females; 71% African-Americans) and 183 HIV-seronegative individuals, with quarterly follow-up visits between 1996 and 2000. Each HLA and CCR variant with consistent risk and protective effect on HIV-1 pathogenesis was assigned a score of -1 and +1, respectively. All individual markers and genetic scores were analyzed in relation to plasma viral load (VL) and CD4 T lymphocytes during a 6-12-month interval when no antiretroviral therapy was taken.
RESULTS - HLA-B*57 alone was a strong predictor of VL (P < 0.0001), but composite genetic profiles found in over 50% of patients consistently outperformed the individual component markers in multivariable analyses with or without adjustment for gender, race, age, and membership of clinical patient groups. Adolescents (n = 37) with a favorable combination of VL (< 1000 copies/ml) and CD4 T cell counts (> 450 x 10(6) cells/l) consistently had more positive (+1 to +2) than negative (-1 to -4) HLA and CCR scores compared with those (n = 56) with an unfavorable combination (VL > 16,000 copies/ml and CD4 cells < 450 x 10(6) cells/l) or the remainder (n = 134) of the cohort (overall P < 0.0001).
CONCLUSION - A generalizable genetic scoring algorithm based on seven HLA class I and CCR markers is highly predictive of viremia and immunodeficiency in HIV-1-infected adolescents.
Copyright 2002 Lippincott Williams & Wilkins
0 Communities
1 Members
0 Resources
20 MeSH Terms
MHC class II alpha/beta heterodimeric cell surface molecules expressed from a single proviral genome.
Shimada H, Germana S, Sonntag KC, Banerjee P, Moore D, Sachs DH, LeGuern C
(1999) Hum Gene Ther 10: 2397-405
MeSH Terms: 3T3 Cells, Animals, Blotting, Northern, Blotting, Southern, Flow Cytometry, Gene Expression, Gene Transfer Techniques, Genes, MHC Class II, Genetic Vectors, HLA-DQ Antigens, Mice, Proviruses, Retroviridae, Reverse Transcriptase Polymerase Chain Reaction, Swine
Show Abstract · Added October 24, 2013
Transplantation tolerance to renal allografts can be induced in large animal preclinical models if the donor and recipient have identical major histocompatibility complex (MHC) class II loci. Such class II matching is, however, not clinically achievable owing to the extreme diversity of class II sequences. With the ultimate goal of creating a somatic class II match in the bone marrow of an allograft recipient, the aim of the study is to develop a double-copy retrovirus construct to express both chains of the MHC class II DQ glycoprotein on a single transduced cell. Analysis of the expression patterns of the retroviral DQ transgenes in both virus producer and transduced fibroblasts revealed correct transcription and stable surface expression of the DQ heterodimers. In addition, we demonstrate that both the DQA and DQB sequences are functional within the same proviral copy, a prerequisite for efficient induction of transplantation tolerance following transduction of bone marrow precursor cells. The DQ double-copy retrovirus vector showed efficient expression of the transferred class II cDNA in murine colony-forming units for the granulocyte-monocyte lineage (CFU-GM), indicating that it is suitable for gene therapy of multimeric proteins in hematopoietic cells.
0 Communities
1 Members
0 Resources
15 MeSH Terms
Distinct IL-4 response mechanisms of the MHC gene A alpha in different mouse B cell lines.
Whitley MZ, Cheng HL, Tomasi TB, Boothby M
(1993) Mol Immunol 30: 821-32
MeSH Terms: Animals, B-Lymphocytes, Gene Expression Regulation, Genes, MHC Class II, Histocompatibility Antigens Class II, Interleukin-4, Mice, RNA, Messenger, Transcription, Genetic, Tumor Cells, Cultured
Show Abstract · Added December 10, 2013
Interleukin-4 (IL-4) is a multipotent cytokine which stimulates proliferation of B and T lymphocytes, induces B lymphocyte expression of major histocompatibility complex (MHC) class II molecules and Fc epsilon R II (CD23) molecules, and promotes immunoglobulin class switching to IgE and IgG1. The mechanisms by which IL-4 induces these changes are unclear. To study the basis for heterogeneity in induction of class II MHC proteins observed in splenic B cells, three mouse B cell lines were treated with IL-4, and the response of MHC class II A alpha mRNA was analyzed. Each of the three cell lines responded with a distinctive profile. In one line, 70Z/3, A alpha mRNA was induced greater than 10 fold by 65 hr of IL-4 stimulation. Additional studies showed that A alpha mRNA was stabilized by IL-4 treatment of 70Z/3 cells, and that changes in gene transcription accounted for little of the increase in mRNA levels. A second line, WEHI.231, was shown to increase A alpha mRNA levels 4 fold after 48 hr of IL-4 treatment. In contrast to 70Z/3, when A alpha mRNA stability in the IL-4 treated WEHI.231 cells was compared to untreated cells, no difference was observed, IL-4 treatment induced A alpha transcription. The third cell line, M12.4.1, expressed high basal levels of A alpha, and these levels increased only slightly following IL-4 stimulation. The small increase correlated with a comparable transcriptional response. These data shown that the nature of the A alpha gene response to IL-4 differs among B cell lines. This heterogeneity of response is consistent with responses in total splenic B cells, and with the existence of functionally distinct subpopulations of B cells.
0 Communities
1 Members
0 Resources
10 MeSH Terms
Amino acid substitutions in the floor of the putative antigen-binding site of H-2T22 affect recognition by a gamma delta T-cell receptor.
Moriwaki S, Korn BS, Ichikawa Y, van Kaer L, Tonegawa S
(1993) Proc Natl Acad Sci U S A 90: 11396-400
MeSH Terms: ATP Binding Cassette Transporter, Subfamily B, Member 2, ATP Binding Cassette Transporter, Subfamily B, Member 3, ATP-Binding Cassette Transporters, Animals, Biological Transport, Carrier Proteins, Genes, MHC Class II, H-2 Antigens, Histocompatibility Antigens Class II, Lymphocyte Activation, Mice, Mutagenesis, Site-Directed, Protein Binding, Protein Structure, Tertiary, Receptors, Antigen, T-Cell, gamma-delta, Recombinant Proteins, Structure-Activity Relationship, Transfection
Show Abstract · Added December 10, 2013
We have previously identified a self-reactive gamma delta T-cell clone (KN6) specific for the H-2T region gene product T22b. Now we have investigated by an in vitro mutagenesis analysis of the T22b gene the possibility that the interaction between the KN6 gamma delta T-cell receptor and T22b involves a peptide. The results demonstrate that mutations at the floor of the putative antigen-binding groove of T22b affect recognition by the gamma delta T-cell receptor. Furthermore, we have shown that KN6 cells react with cells that are deficient in the class I peptide transporter TAP1/TAP2. These results suggest that peptide is involved in the interaction of the KN6 T-cell receptor with T22 and that loading of T22 with the putative peptide is TAP1/TAP2-independent.
0 Communities
1 Members
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18 MeSH Terms
Altered peptidase and viral-specific T cell response in LMP2 mutant mice.
Van Kaer L, Ashton-Rickardt PG, Eichelberger M, Gaczynska M, Nagashima K, Rock KL, Goldberg AL, Doherty PC, Tonegawa S
(1994) Immunity 1: 533-41
MeSH Terms: Animals, Antigen Presentation, Antigen-Presenting Cells, Antigens, Viral, CD8-Positive T-Lymphocytes, Cysteine Endopeptidases, Genes, MHC Class II, Histocompatibility Antigens Class I, Liver, Mice, Mice, Knockout, Orthomyxoviridae, Parainfluenza Virus 1, Human, Peptide Hydrolases, Proteins, Spleen, T-Lymphocyte Subsets, T-Lymphocytes, T-Lymphocytes, Cytotoxic
Show Abstract · Added December 10, 2013
MHC class I molecules present peptides generated by processing of endogenously synthesized proteins to CD8+ T lymphocytes. Recently, large proteolytic complexes, termed proteasomes, were implicated in antigen processing. Two proteasomal subunits, LMP2 and LMP7, are encoded within the MHC class II region, but their precise role in antigen processing is unknown. We have generated mice that harbor a disruption in their LMP2 gene. Proteasomes purified from spleen and liver of these mutant mice exhibit altered peptidase activities, and antigen-presenting cells showed reduced capacity to stimulate a T cell hybridoma specific for H-2Db plus a nucleoprotein epitope of an influenza A virus. The mutant mice have reduced (60%-70% of wild type) levels of CD8+ T lymphocytes and generate 5- to 6-fold fewer influenza nucleoprotein-specific cytotoxic T lymphocyte precursors. These findings indicate that LMP2 influences antigen processing.
0 Communities
1 Members
0 Resources
19 MeSH Terms
A human Ia cytoplasmic determinant located on multiple forms of invariant chain (gamma, gamma 2, gamma 3).
Quaranta V, Majdic O, Stingl G, Liszka K, Honigsmann H, Knapp W
(1984) J Immunol 132: 1900-5
MeSH Terms: Animals, Antibodies, Monoclonal, B-Lymphocytes, Cytoplasm, Electrophoresis, Polyacrylamide Gel, Epitopes, Fluorescent Antibody Technique, Genes, MHC Class II, Histocompatibility Antigens Class II, Humans, Mice, Mice, Inbred BALB C, Polymorphism, Genetic, Rabbits
Show Abstract · Added March 27, 2014
An antigenic determinant present in the cytoplasm, but not on the surface membrane of human Ia+ cells, is defined by a monoclonal antibody (VIC-Y1) and is shown by immunoprecipitation and by NEPHGE to be expressed by Ia oligomers. Immunoprecipitations of cellfree translates and of purified Ia subunits indicate that the VIC-Y1 determinant is located on the Ia gamma-(invariant) chain, as well as on two other related molecules, provisionally termed gamma 2 and gamma 3. Within our experimental conditions, the three forms of gamma-chains co-precipitate exclusively with Ia oligomers. As detected by VIC-Y1 and in the limits of our assays, gamma-chains could not be found at the cell surface; their tissue distribution, determined by cytoplasmic indirect immunofluorescence with VIC-Y1, closely resembles that of Ia antigens, with the possible exception of acute lymphatic leukemia cells (Ia+, gamma-chain-).
1 Communities
1 Members
0 Resources
14 MeSH Terms