107 results on '"Henegariu O"'
Search Results
2. Analysis of Human Biologics With a Mouse Skin Transplant Model in Humanized Mice
- Author
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Waldron-Lynch, F., Deng, S., Preston-Hurlburt, P., Henegariu, O., and Herold, K.C.
- Published
- 2012
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3. Triple-color FISH analysis of 12p amplification in testicular germ-cell tumors using 12p band-specific painting probes
- Author
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Henegariu, O., Vance, Gail H., Heiber, Devan, Pera, Martin, and Heerema, Nyla A.
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- 1998
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4. Cryptic Translocation Identification in Human and Mouse using Several Telomeric Multiplex FISH (TM-FISH) Strategies
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Henegariu, O, primary, Artan, S, additional, Greally, J M, additional, Chen, X-N, additional, Korenberg, J R, additional, Vance, G H, additional, Stubbs, L, additional, Bray-Ward, P, additional, and Ward, D C, additional
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- 2003
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5. HOW DOES THE SILENCING OF THE INFLAMMATION MEDIATOR GENE: FAT10, EXTEND LIFESPAN IN MICE?
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Canaan, A., primary, Arjona, C., additional, Gulez, B., additional, Seay, M., additional, Zhang, J., additional, Henegariu, O., additional, and Garcia Milian, R., additional
- Published
- 2017
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6. Histological comparisons of testicular germ cell tumors by CGH analysis
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Smith, L.R., Henegariu, O., Thurston, V.C., and Vance, G.H.
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Genetic disorders -- Research ,Germ cell tumors -- Genetic aspects ,Histology, Pathological -- Research ,Biological sciences - Published
- 2001
7. HOW DOES THE SILENCING OF THE INFLAMMATION MEDIATOR GENE: FAT10, EXTEND LIFESPAN IN MICE?
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Gulez B, Henegariu O, Zhang J, Garcia Milian R, Arjona C, Seay M, and Canaan A
- Subjects
Health (social science) ,business.industry ,Inflammation ,Biology ,Health Professions (miscellaneous) ,Cell biology ,Abstracts ,Text mining ,Mediator ,medicine ,Gene silencing ,medicine.symptom ,Life-span and Life-course Studies ,business ,Gene - Abstract
FAT10 knockout mice display 50% reduction in total body fat and 20% increase in median and maximal lifespan, in both sexes. It is still unclear how FAT10 silencing affects aging and metabolism. Our current studies provide novel mechanistic insights for the role of this inflammation related gene - FAT10 in aging and metabolism.
- Published
- 2017
8. Enhanced anti-serpin activity inhibits autoimmune inflammation of type 1 diabetes
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Czyzyk, J., Henegariu, O., Preston-Hurlburt, P., Baldzizhar, R., Fedorchuk, C., Espluges, E., Frans Gorus, Bottomly, K., Herold, K., Flavell, R., and Pathologic Biochemistry and Physiology
- Subjects
type 1 diabetes - Abstract
Intracellular (clade B) OVA-serpin protease inhibitors play an important role in tissue homeostasis by protecting cells from death in response to hypo-osmotic stress, heat shock, and other stimuli. It is not known whether these serpins influence immunological tolerance and the risk for autoimmune diseases. We found that a fraction of young autoimmune diabetes-prone NOD mice had elevated levels of autoantibodies against a member of clade B family known as serpinB13. High levels of anti-serpinB13 Abs were accompanied by low levels of anti-insulin autoantibodies, reduced numbers of islet-associated T cells, and delayed onset of diabetes. Exposure to anti-serpinB13 mAb alone also decreased islet inflammation, and coadministration of this reagent and a suboptimal dose of anti-CD3 mAb accelerated recovery from diabetes. In a fashion similar to that discovered in the NOD model, a deficiency in humoral activity against serpinB13 was associated with early onset of human type 1 diabetes. These findings suggest that, inaddition to limiting exposure to proteases within the cell, clade B serpins help to maintain homeostasis by inducing protective humoral immunity.
- Published
- 2012
9. Triple-color FISH analysis of 12p amplification in testicular germ-cell tumors using 12p band-specific painting probes.
- Author
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Heiber D., Heerema N.A., Pera M., Henegariu O., Vance G.H., Heiber D., Heerema N.A., Pera M., Henegariu O., and Vance G.H.
- Abstract
Forty-nine surgical specimens and nine germ cell tumor lines were analyzed by triple-color FISH using microdissected probes for the cytogenetic bands of chromosome arm 12p (12p11.2, p12, and p13). FISH analysis demonstrated amplification of material from all three bands in all tumors. This amplification was in the form of increased copy number of 12p or i(12p) and/or 12p amplified regions (AMP12p). The number of copies of 12p was variable (4-11 copies) from case to case but tended to remain relatively constant in all clones of the same tumor, even when the amplification took the form of an amplified region composed of 12p material. In tumors with multiple clones, i(12p) and AMP12p were never found in the same cell. No correlation was found between 12p copy number and tumor type. We describe, for the fist time, a relative overrepresentation of 12p13 or 12p12-p13 regions in six tumors (two surgical samples and four cell lines), either as 'partial 12p' (five cases) or within a 12p amplified region (one case). The ubiquitous amplification of all three 12p bands in germ-cell tumors supports the hypothesis that 12p harbors more than one gene important for oncogenesis of adult male germ-cell tumors, and that these genes may be located in different areas of 12p.
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- 2012
10. Characterization of gains, losses, and regional amplification in testicular germ cell tumor cell lines by comparative genomic hybridization.
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Vance G.H., Henegariu O., Heerema N.A., Thurston V., Jung S.-H., Pera M., Vance G.H., Henegariu O., Heerema N.A., Thurston V., Jung S.-H., and Pera M.
- Abstract
We have performed comparative genomic hybridization on 12 testicular germ cell tumor (TGCT) cell lines and one paraffin-embedded surgical specimen to identify and characterize genome-wide gains and losses of chromosomes in these specimens. All specimens demonstrated overrepresentation of 12p. Other significant chromosomal gains, apart from 12p, included the X chromosome and chromosome arms 1q and 20q. Chromosomal losses were observed for chromosomes 4 and 18 and chromosome arms 2q, 9q, and 13q. Genomic differences were observed between an embryonal carcinoma component of a mixed tumor, 833K, and its cisplastin-resistant derivative line, 64CP, including losses of 6q23~qter and 9p22~q21. Five lines also demonstrated gain of 12p and additional 12p12~p13 material. Similarly, two lines demonstrated gain of 12p and additional 12p11.2~p12 material. The data supports the consistent gain of 12p in adult TGCT cell lines and additional regional amplification of 12p in some lines. This regional amplification has been observed in both primary tumor specimens and TGCT cell lines and may support a hypothesis that at least two different regions of 12p, one proximal and one distal, harbor genes important for the pathogenesis of testicular germ cell neoplasia. © 2004 Elsevier Inc. All rights reserved.
- Published
- 2012
11. P.1.i.040 Increased expression of diabetic autoantigen PTPR-N in basal ganglia of Tourette's syndrome patients
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Morer, A., primary, Chae, W., additional, Tobiasova, Z., additional, Henegariu, O., additional, Vaccarino, F., additional, Bothwell, A., additional, Leckman, J.F., additional, and Kawikova, I., additional
- Published
- 2009
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12. Rapid screening of the Y chromosome in idiopathic sterile men, diagnostic for deletions in AZF, a genetic Y factor expressed during spermatogenesis
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Henegariu, O., primary, Hirschmann, P., additional, Kilian, K., additional, Kirsch, S., additional, Lengauer, C., additional, Maiwald, R., additional, Mielke, K., additional, and Vogt, P., additional
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- 2009
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13. Rapid DNA Fiber Technique for Size Measurements of Linear and Circular DNA Probes
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Henegariu, O., primary, Grober, L., additional, Haskins, W., additional, Bowers, P.N., additional, State, M.W., additional, Ohmido, N., additional, Bray-Ward, P., additional, and Ward, D.C., additional
- Published
- 2001
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14. Multiplex PCR: Critical Parameters and Step-by-Step Protocol
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Henegariu, O., primary, Heerema, N.A., additional, Dlouhy, S.R., additional, Vance, G.H., additional, and Vogt, P.H., additional
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- 1997
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15. Molecular analysis of the genomic structure of the human Y chromosome in the euchromatic part of its long arm (Yq11)
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Kirsch, S., primary, Keil, R., additional, Edelmann, A., additional, Henegariu, O., additional, Hirschmann, P., additional, LePaslier, D., additional, and Vogt, P.H., additional
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- 1996
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16. Synergistic reversal of type 1 diabetes in NOD mice with anti-CD3 and interleukin-1 blockade: evidence of improved immune regulation.
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Ablamunits V, Henegariu O, Hansen JB, Opare-Addo L, Preston-Hurlburt P, Santamaria P, Mandrup-Poulsen T, Herold KC, Ablamunits, Vitaly, Henegariu, Octavian, Hansen, Jakob Bondo, Opare-Addo, Lynn, Preston-Hurlburt, Paula, Santamaria, Pere, Mandrup-Poulsen, Thomas, and Herold, Kevan C
- Abstract
Inflammatory cytokines are involved in autoimmune diabetes: among the most prominent is interleukin (IL)-1β. We postulated that blockade of IL-1β would modulate the effects of anti-CD3 monoclonal antibody (mAb) in treating diabetes in NOD mice. To test this, we treated hyperglycemic NOD mice with F(ab')(2) fragments of anti-CD3 mAb with or without IL-1 receptor antagonist (IL-1RA), or anti-IL-1β mAb. We studied the reversal of diabetes and effects of treatment on the immune system. Mice that received a combination of anti-CD3 mAb with IL-1RA showed a more rapid rate of remission of diabetes than mice treated with anti-CD3 mAb or IL-1RA alone. Combination-treated mice had increased IL-5, IL-4, and interferon (IFN)-γ levels in circulation. There were reduced pathogenic NOD-relevant V7 peptide-V7(+) T cells in the pancreatic lymph nodes. Their splenocytes secreted more IL-10, had increased arginase expression in macrophages and dendritic cells, and had delayed adoptive transfer of diabetes. After 1 month, there were increased concentrations of IgG1 isotype antibodies and reduced intrapancreatic expression of IFN-γ, IL-6, and IL-17 despite normal splenocyte cytokine secretion. These studies indicate that the combination of anti-CD3 mAb with IL-1RA is synergistic in reversal of diabetes through a combination of mechanisms. The combination causes persistent remission from islet inflammation. [ABSTRACT FROM AUTHOR]
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- 2012
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17. Molecular analysis of the genomic structure of the human Y chromosome in the euchromatic part of its long arm (Yq11).
- Author
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Kirsch, S., Keil, R., Edelmann, A., Henegariu, O., Hirschmann, P., LePaslier, D., and Vogt, P.H.
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- 1996
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18. Human Y Chromosome Azoospermia Factors (AZF) Mapped to Different Subregions in Yq11.
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Vog, P. H., Edelmann, A., Kirsch, S., Henegariu, O., Hirschmann, P., Kiesewetter, F., Köhn, F. M., Schill, W. B., Farah, S., Ramos, C., Hartmann, M., Hartschuh, W., Meschede, D., Behre, H. M., Castel, A., Nieschlag, E., Weidner, W., Gröne, H-J., Jung, A., and Engel, W.
- Published
- 1996
19. Characterization of Multiple 12p Rearrangements in Testicular Germ Cell Tumor Cell Line 833K and Its Subclone 64CP by Chromosome Microdissection
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Blough, R. I., Vance, G. H., Henegariu, O., Smolarek, T. A., Sledge, G. W., and Heerema, N. A.
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- 1998
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20. Protein-tyrosine phosphatase Shp-2 regulates cell spreading, migration, and focal adhesion.
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Yu, D H, Qu, C K, Henegariu, O, Lu, X, and Feng, G S
- Abstract
Shp-2, a widely expressed cytoplasmic tyrosine phosphatase with two SH2 domains, is believed to participate in signal relay downstream of growth factor receptors. We show here that this phosphatase also plays an important role in the control of cell spreading, migration, and cytoskeletal architecture. Fibroblast cells lacking a functional Shp-2 were impaired in their ability to spread and migrate on fibronectin compared with wild-type cells. Furthermore, Shp-2 mutant cells displayed an increased number of focal adhesions and condensed F-actin aggregation at the cell periphery, properties reminiscent of focal adhesion kinase (FAK)-deficient cells. This is consistent with our previous observations in vivo that mice homozygous for the Shp-2 mutation died at midgestation with similar phenotype to FAK and fibronectin-deficient embryos, having severe defects in mesodermal patterning, particularly the truncation of posterior structures. Biochemical analysis demonstrated that FAK dephosphorylation was significantly reduced in Shp-2 mutant cells in suspension. Furthermore, regulated association of Src SH2 domain with FAK and paxillin during cell attachment and detachment on fibronectin was disrupted in Shp-2 mutant cells. This report defines a unique role of the Shp-2 tyrosine phosphatase in cell motility, which might guide the design of a new strategy for pharmaceutical interference of tumor metastasis.
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- 1998
21. Alteration in expression of the rat mitochondrial ATPase 6 gene during Pneumocystis carinii infection
- Author
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Bartlett Marilyn S, Goheen Michael P, Shaw Margaret M, Henegariu Octavian, Asnicar Mark A, Smith James W, and Lee Chao-Hung
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Microbiology ,QR1-502 - Abstract
Abstract Background Pneumocystis carinii causes pneumonia in immunocompromised patients with a high morbidity and mortality rate, but the interaction between this organism and the host cell is not well understood. The purpose of this research was to study the response of host cells to P. carinii infection on a molecular level. Results The technique of mRNA differential display was used to detect genes whose expression may be affected by P. carinii infection. The nucleotide sequence of one differentially displayed DNA fragment was found to be identical to that of the rat mitochondrial ATPase 6 gene, which is a subunit of the F0F1-ATP synthase complex. A four-fold increase in expression of this gene was verified by Northern blot analysis of total RNA extracted from P. carinii-infected rat lung versus that from mock-infected rat lung. Localization of the cells containing ATPase 6 mRNA was accomplished by in situ hybridization. In sections of non-infected rat lung, these cells were found lining the distal parts of the respiratory tree and in apical areas of the alveoli. Histological location of these cells suggested that they were Clara cells and type II pneumocytes. This hypothesis was confirmed by co-localizing the mRNAs for ATPase 6 and surfactant protein B (SP-B) to the same cells by two-color fluorescent in situ hybridization. Conclusions The ATPase 6 gene is over expressed during P. carinii infection, and type II pneumocytes and Clara cells are the cell types responsible for this over-expression.
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- 2001
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22. Reply to Pisan et al.: Pathogenicity of inherited TRAF7 mutations in congenital heart disease.
- Author
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Mishra-Gorur K, Barak T, Kaulen LD, Henegariu O, Jin SC, Aguilera SM, Yalbir E, Goles G, Nishimura S, Miyagishima D, Djenoune L, Altinok S, Rai DK, Viviano S, Prendergast A, Zerillo C, Ozcan K, Baran B, Sencar L, Goc N, Yarman Y, Ercan-Encicek AG, Bilguvar K, Lifton RP, Moliterno J, Louvi A, Yuan S, Deniz E, Brueckner M, and Gunel M
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- Humans, Virulence, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Germ-Line Mutation, Heart Defects, Congenital genetics
- Abstract
Competing Interests: Competing interests statement:The authors declare no competing interest.
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- 2024
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23. Thrombocyte-derived Dickkopf1 promotes macrophage polarization in the Bleomycin-induced lung injury model.
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Sung EA, Park MH, Song S, Alanya H, Henegariu O, Liu J, Erson-Omay EZ, Sime PJ, and Chae WJ
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- Animals, Mice, Bleomycin adverse effects, Inflammation, Interleukin-13 metabolism, Acute Lung Injury metabolism, Blood Platelets metabolism, Macrophages
- Abstract
Immune responses are crucial to maintaining tissue homeostasis upon tissue injury. Upon various types of challenges, macrophages play a central role in regulating inflammation and tissue repair processes. While an immunomodulatory role of Wnt antagonist Dickkopf1 (DKK1) has been implicated, the role of Wnt antagonist DKK1 in regulating macrophage polarization in inflammation and the tissue repair process remains elusive. Here we found that DKK1 induces gene expression profiles to promote inflammation and tissue repair in macrophages. Importantly, DKK1 induced various genes, including inflammation and tissue repair, via JNK (c-jun N-terminal kinase) in macrophages. Furthermore, DKK1 potentiated IL-13-mediated macrophage polarization and activation. The co-inhibition of JNK and STAT6 markedly decreased gene expressions relevant to inflammation and fibrosis by DKK1 and IL-13. Interestingly, thrombocyte-specific deletion of DKK1 in mice reduced collagen deposition and decreased Arg1, CD206, HIF1α, and IL1β protein expressions in monocyte-derived alveolar macrophages in the acute sterile bleomycin (BLM)-induced lung injury model. These data suggested that thrombocytes communicate with macrophages via DKK1 to orchestrate inflammation and repair in this model. Taken together, our study demonstrates DKK1's role as an important regulatory ligand for macrophage polarization in the injury-induced inflammation and repair process in the lung., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sung, Park, Song, Alanya, Henegariu, Liu, Erson-Omay, Sime and Chae.)
- Published
- 2023
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24. Dickkopf1 Promotes Pulmonary Fibrosis upon Bleomycin-Induced Lung Injury.
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Sung EA, Park MH, Henegariu O, Sime PJ, and Chae WJ
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- Humans, Mice, Animals, Bleomycin toxicity, Lung pathology, Transforming Growth Factor beta1 metabolism, Collagen metabolism, Inflammation pathology, Pulmonary Fibrosis pathology, Lung Injury pathology, Pneumonia metabolism
- Abstract
Orchestration of inflammation and tissue repair processes is critical to maintaining homeostasis upon tissue injury. Tissue fibrosis is a pathological process characterized by aberrant accumulation of extracellular matrix proteins, such as collagen, upon injury. Dickkopf1 (DKK1) is a quintessential Wnt antagonist. The role of DKK1 in bleomycin (BLM)-induced lung injury and fibrosis model remains elusive. This study shows that BLM-induced lung injury markedly elevated DKK1 protein expressions in the lungs in mice, consistent with human pulmonary fibrosis patient lung tissues. The elevated DKK1 levels coincided with immune cell infiltration and collagen deposition. Notably, the reduced expression of DKK1 in Dkk1 hypomorphic doubleridge (Dkk1
d/d ) mice abrogated BLM-induced lung inflammation and fibrosis. Immune cell infiltration, collagen deposition, expression of profibrotic cytokine transforming growth factor β1 (TGF-β1), and extracellular matrix protein-producing myofibroblast marker α-smooth muscle actin (α-SMA) were reduced in Dkk1d/d mice. Consistent with these results, local DKK1 antibody administration after BLM-induced lung injury substantially decreased lung inflammation and fibrosis phenotypes. Taken together, these results demonstrate that DKK1 is a proinflammatory and profibrotic ligand that promotes inflammation and fibrosis upon BLM-induced lung injury, placing it as an attractive molecular target for dysregulated pulmonary inflammation and tissue repair., (Copyright © 2023 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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25. Integrated genetic analyses of immunodeficiency-associated Epstein-Barr virus- (EBV) positive primary CNS lymphomas.
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Kaulen LD, Denisova E, Hinz F, Hai L, Friedel D, Henegariu O, Hoffmann DC, Ito J, Kourtesakis A, Lehnert P, Doubrovinskaia S, Karschnia P, von Baumgarten L, Kessler T, Baehring JM, Brors B, Sahm F, and Wick W
- Subjects
- Humans, Herpesvirus 4, Human genetics, Mutation, Prognosis, Tumor Microenvironment, Epstein-Barr Virus Infections genetics, Epstein-Barr Virus Infections metabolism, Lymphoma genetics
- Abstract
Immunodeficiency-associated primary CNS lymphoma (PCNSL) represents a distinct clinicopathological entity, which is typically Epstein-Barr virus-positive (EBV
+ ) and carries an inferior prognosis. Genetic alterations that characterize EBV-related CNS lymphomagenesis remain unclear precluding molecular classification and targeted therapies. In this study, a comprehensive genetic analysis of 22 EBV+ PCNSL, therefore, integrated clinical and pathological information with exome and RNA sequencing (RNASeq) data. EBV+ PCNSL with germline controls carried a median of 55 protein-coding single nucleotide variants (SNVs; range 24-217) and 2 insertions/deletions (range 0-22). Genetic landscape was largely shaped by aberrant somatic hypermutation with a median of 41.01% (range 31.79-53.49%) of SNVs mapping to its target motifs. Tumors lacked established SNVs (MYD88, CD79B, PIM1) and copy number variants (CDKN2A, HLA loss) driving EBV- PCNSL. Instead, EBV+ PCNSL were characterized by SOCS1 mutations (26%), predicted to disinhibit JAK/STAT signaling, and mutually exclusive gain-of-function NOTCH pathway SNVs (26%). Copy number gains were enriched on 11q23.3, a locus directly targeted for chromosomal aberrations by EBV, that includes SIK3 known to protect from cytotoxic T-cell responses. Losses covered 5q31.2 (STING), critical for sensing viral DNA, and 17q11 (NF1). Unsupervised clustering of RNASeq data revealed two distinct transcriptional groups, that shared strong expression of CD70 and IL1R2, previously linked to tolerogenic tumor microenvironments. Correspondingly, deconvolution of bulk RNASeq data revealed elevated M2-macrophage, T-regulatory cell, mast cell and monocyte fractions in EBV+ PCNSL. In addition to novel insights into the pathobiology of EBV+ PCNSL, the data provide the rationale for the exploration of targeted therapies including JAK-, NOTCH- and CD70-directed approaches., (© 2023. The Author(s).)- Published
- 2023
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26. Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.
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Mishra-Gorur K, Barak T, Kaulen LD, Henegariu O, Jin SC, Aguilera SM, Yalbir E, Goles G, Nishimura S, Miyagishima D, Djenoune L, Altinok S, Rai DK, Viviano S, Prendergast A, Zerillo C, Ozcan K, Baran B, Sencar L, Goc N, Yarman Y, Ercan-Sencicek AG, Bilguvar K, Lifton RP, Moliterno J, Louvi A, Yuan S, Deniz E, Brueckner M, and Gunel M
- Subjects
- Animals, Adaptor Proteins, Signal Transducing metabolism, Mutation, Skull metabolism, Zebrafish genetics, Zebrafish metabolism, Zebrafish Proteins genetics, Humans, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Heart Defects, Congenital genetics, Meningeal Neoplasms genetics, Meningioma genetics, Meningioma pathology
- Abstract
While somatic variants of TRAF7 (Tumor necrosis factor receptor-associated factor 7) underlie anterior skull-base meningiomas, here we report the inherited mutations of TRAF7 that cause congenital heart defects. We show that TRAF7 mutants operate in a dominant manner, inhibiting protein function via heterodimerization with wild-type protein. Further, the shared genetics of the two disparate pathologies can be traced to the common origin of forebrain meninges and cardiac outflow tract from the TRAF7- expressing neural crest. Somatic and inherited mutations disrupt TRAF7-IFT57 interactions leading to cilia degradation. TRAF7 -mutant meningioma primary cultures lack cilia, and TRAF7 knockdown causes cardiac, craniofacial, and ciliary defects in Xenopus and zebrafish, suggesting a mechanistic convergence for TRAF7 -driven meningiomas and developmental heart defects.
- Published
- 2023
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27. PPIL4 is essential for brain angiogenesis and implicated in intracranial aneurysms in humans.
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Barak T, Ristori E, Ercan-Sencicek AG, Miyagishima DF, Nelson-Williams C, Dong W, Jin SC, Prendergast A, Armero W, Henegariu O, Erson-Omay EZ, Harmancı AS, Guy M, Gültekin B, Kilic D, Rai DK, Goc N, Aguilera SM, Gülez B, Altinok S, Ozcan K, Yarman Y, Coskun S, Sempou E, Deniz E, Hintzen J, Cox A, Fomchenko E, Jung SW, Ozturk AK, Louvi A, Bilgüvar K, Connolly ES Jr, Khokha MK, Kahle KT, Yasuno K, Lifton RP, Mishra-Gorur K, Nicoli S, and Günel M
- Subjects
- Cyclophilins physiology, Humans, Mutation, RNA-Binding Proteins physiology, Exome Sequencing, Wnt Signaling Pathway physiology, Brain blood supply, Cyclophilins genetics, Intracranial Aneurysm genetics, Neovascularization, Pathologic genetics, RNA-Binding Proteins genetics
- Abstract
Intracranial aneurysm (IA) rupture leads to subarachnoid hemorrhage, a sudden-onset disease that often causes death or severe disability. Although genome-wide association studies have identified common genetic variants that increase IA risk moderately, the contribution of variants with large effect remains poorly defined. Using whole-exome sequencing, we identified significant enrichment of rare, deleterious mutations in PPIL4, encoding peptidyl-prolyl cis-trans isomerase-like 4, in both familial and index IA cases. Ppil4 depletion in vertebrate models causes intracerebral hemorrhage, defects in cerebrovascular morphology and impaired Wnt signaling. Wild-type, but not IA-mutant, PPIL4 potentiates Wnt signaling by binding JMJD6, a known angiogenesis regulator and Wnt activator. These findings identify a novel PPIL4-dependent Wnt signaling mechanism involved in brain-specific angiogenesis and maintenance of cerebrovascular integrity and implicate PPIL4 gene mutations in the pathogenesis of IA., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2021
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28. Exome sequencing identifies SLIT2 variants in primary CNS lymphoma.
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Kaulen LD, Erson-Omay EZ, Henegariu O, Karschnia P, Huttner A, Günel M, and Baehring JM
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- Central Nervous System Neoplasms pathology, Central Nervous System Neoplasms virology, Cohort Studies, Female, Genomic Structural Variation genetics, Genomics methods, Herpesvirus 4, Human genetics, Humans, Lymphoma, Non-Hodgkin diagnosis, Lymphoma, Non-Hodgkin drug therapy, Lymphoma, Non-Hodgkin mortality, Male, NF-kappa B genetics, Prognosis, Progression-Free Survival, Retrospective Studies, Central Nervous System Neoplasms genetics, Intercellular Signaling Peptides and Proteins genetics, Lymphoma, Non-Hodgkin genetics, Nerve Tissue Proteins genetics, Exome Sequencing methods
- Abstract
SLIT2 constitutes a known tumour suppressor gene, which has not yet been implicated in the pathogenesis of primary central nervous system lymphoma (PCNSL). Performing exome sequencing on paired blood and tumour DNA samples from six treatment-naïve PCNSL patients, we identified novel SLIT2 variants (p.N63S, p.T590M, p.T732S) that were associated with shorter progression-free survival in our cohort and shorter overall survival in a large validation cohort of lymphoid malignancies from the cBio Cancer Genomics Portal. WNT- and NF-κB-reporter luciferase assays suggest detected alterations are loss-of-function variants. Given the possible prognostic implications, the role of SLIT2 in PCNSL pathogenesis and progression warrants further investigation., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2021
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29. Integrated genomic analyses of de novo pathways underlying atypical meningiomas.
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Harmancı AS, Youngblood MW, Clark VE, Coşkun S, Henegariu O, Duran D, Erson-Omay EZ, Kaulen LD, Lee TI, Abraham BJ, Simon M, Krischek B, Timmer M, Goldbrunner R, Omay SB, Baranoski J, Baran B, Carrión-Grant G, Bai H, Mishra-Gorur K, Schramm J, Moliterno J, Vortmeyer AO, Bilgüvar K, Yasuno K, Young RA, and Günel M
- Abstract
This corrects the article DOI: 10.1038/ncomms14433.
- Published
- 2018
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30. Membrane-bound Dickkopf-1 in Foxp3 + regulatory T cells suppresses T-cell-mediated autoimmune colitis.
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Chae WJ, Park JH, Henegariu O, Yilmaz S, Hao L, and Bothwell ALM
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- Adoptive Transfer, Animals, Autoimmune Diseases genetics, Autoimmune Diseases immunology, Autoimmune Diseases pathology, Autoimmunity, CHO Cells, Cell Membrane immunology, Cell Proliferation, Colitis genetics, Colitis immunology, Colitis pathology, Colon immunology, Colon pathology, Cricetulus, DNA-Binding Proteins deficiency, DNA-Binding Proteins genetics, Disease Models, Animal, Forkhead Transcription Factors genetics, Forkhead Transcription Factors immunology, Genetic Predisposition to Disease, Intercellular Signaling Peptides and Proteins deficiency, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins immunology, Lymphocyte Activation, Mice, Inbred C57BL, Mice, Knockout, Mitogen-Activated Protein Kinases metabolism, Phenotype, Signal Transduction, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory transplantation, Time Factors, Transfection, Autoimmune Diseases metabolism, Cell Membrane metabolism, Colitis metabolism, Colon metabolism, Forkhead Transcription Factors metabolism, Intercellular Signaling Peptides and Proteins metabolism, Self Tolerance, T-Lymphocytes, Regulatory metabolism
- Abstract
Induction of tolerance is a key mechanism to maintain or to restore immunological homeostasis. Here we show that Foxp3
+ regulatory T (Treg) cells use Dickkopf-1 (DKK-1) to regulate T-cell-mediated tolerance in the T-cell-mediated autoimmune colitis model. Treg cells from DKK-1 hypomorphic doubleridge mice failed to control CD4+ T-cell proliferation, resulting in CD4 T-cell-mediated autoimmune colitis. Thymus-derived Treg cells showed a robust expression of DKK-1 but not in naive or effector CD4 T cells. DKK-1 expression in Foxp3+ Treg cells was further increased upon T-cell receptor stimulation in vitro and in vivo. Interestingly, Foxp3+ Treg cells expressed DKK-1 in the cell membrane and the functional inhibition of DKK-1 using DKK-1 monoclonal antibody abrogated the suppressor function of Foxp3+ Treg cells. DKK-1 expression was dependent on de novo protein synthesis and regulated by the mitogen-activated protein kinase pathway but not by the canonical Wnt pathway. Taken together, our results highlight membrane-bound DKK-1 as a novel Treg-derived mediator to maintain immunological tolerance in T-cell-mediated autoimmune colitis., (© 2017 The Authors. Immunology Published by John Wiley & Sons Ltd.)- Published
- 2017
- Full Text
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31. Integrated genomic analyses of de novo pathways underlying atypical meningiomas.
- Author
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Harmancı AS, Youngblood MW, Clark VE, Coşkun S, Henegariu O, Duran D, Erson-Omay EZ, Kaulen LD, Lee TI, Abraham BJ, Simon M, Krischek B, Timmer M, Goldbrunner R, Omay SB, Baranoski J, Baran B, Carrión-Grant G, Bai H, Mishra-Gorur K, Schramm J, Moliterno J, Vortmeyer AO, Bilgüvar K, Yasuno K, Young RA, and Günel M
- Subjects
- Binding Sites, Brain Neoplasms genetics, Brain Neoplasms metabolism, Cell Transformation, Neoplastic genetics, Chromosomal Instability, Cluster Analysis, DNA Methylation, E2F2 Transcription Factor metabolism, Enhancer of Zeste Homolog 2 Protein metabolism, Epigenomics methods, Exome genetics, Forkhead Box Protein M1 metabolism, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Silencing, Genes, Neurofibromatosis 2, Genotyping Techniques, Human Embryonic Stem Cells metabolism, Humans, Jumonji Domain-Containing Histone Demethylases genetics, Molecular Probe Techniques, Mutation, Phenotype, Polycomb Repressive Complex 2 genetics, Polycomb Repressive Complex 2 metabolism, Promoter Regions, Genetic, RNA, Messenger metabolism, SMARCB1 Protein genetics, Sequence Analysis, Signal Transduction genetics, Transcriptome, Gene Regulatory Networks genetics, Gene Regulatory Networks physiology, Genome, Genomics methods, Meningeal Neoplasms genetics, Meningeal Neoplasms metabolism, Meningioma genetics, Meningioma metabolism
- Abstract
Meningiomas are mostly benign brain tumours, with a potential for becoming atypical or malignant. On the basis of comprehensive genomic, transcriptomic and epigenomic analyses, we compared benign meningiomas to atypical ones. Here, we show that the majority of primary (de novo) atypical meningiomas display loss of NF2, which co-occurs either with genomic instability or recurrent SMARCB1 mutations. These tumours harbour increased H3K27me3 signal and a hypermethylated phenotype, mainly occupying the polycomb repressive complex 2 (PRC2) binding sites in human embryonic stem cells, thereby phenocopying a more primitive cellular state. Consistent with this observation, atypical meningiomas exhibit upregulation of EZH2, the catalytic subunit of the PRC2 complex, as well as the E2F2 and FOXM1 transcriptional networks. Importantly, these primary atypical meningiomas do not harbour TERT promoter mutations, which have been reported in atypical tumours that progressed from benign ones. Our results establish the genomic landscape of primary atypical meningiomas and potential therapeutic targets.
- Published
- 2017
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32. Longitudinal analysis of treatment-induced genomic alterations in gliomas.
- Author
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Erson-Omay EZ, Henegariu O, Omay SB, Harmancı AS, Youngblood MW, Mishra-Gorur K, Li J, Özduman K, Carrión-Grant G, Clark VE, Çağlar C, Bakırcıoğlu M, Pamir MN, Tabar V, Vortmeyer AO, Bilguvar K, Yasuno K, DeAngelis LM, Baehring JM, Moliterno J, and Günel M
- Subjects
- Antineoplastic Agents therapeutic use, Combined Modality Therapy, DNA Mismatch Repair, DNA Mutational Analysis, DNA, Neoplasm, Disease Progression, Exome, Female, General Surgery, Genome, Human, Glioblastoma genetics, Glioblastoma pathology, Humans, Immunotherapy, Longitudinal Studies, Middle Aged, Mutation, Radiotherapy, Treatment Outcome, Chromosome Aberrations, Genomics, Glioblastoma therapy, Neoplasm Recurrence, Local, Precision Medicine
- Abstract
Background: Glioblastoma multiforme (GBM) constitutes nearly half of all malignant brain tumors and has a median survival of 15 months. The standard treatment for these lesions includes maximal resection, radiotherapy, and chemotherapy; however, individual tumors display immense variability in their response to these approaches. Genomic techniques such as whole-exome sequencing (WES) provide an opportunity to understand the molecular basis of this variability., Methods: Here, we report WES-guided treatment of a patient with a primary GBM and two subsequent recurrences, demonstrating the dynamic nature of treatment-induced molecular changes and their implications for clinical decision-making. We also analyze the Yale-Glioma cohort, composed of 110 whole exome- or whole genome-sequenced tumor-normal pairs, to assess the frequency of genomic events found in the presented case., Results: Our longitudinal analysis revealed how the genomic profile evolved under the pressure of therapy. Specifically targeted approaches eradicated treatment-sensitive clones while enriching for resistant ones, generated due to chromothripsis, which we show to be a frequent event in GBMs based on our extended analysis of 110 gliomas in the Yale-Glioma cohort. Despite chromothripsis and the later acquired mismatch-repair deficiency, genomics-guided personalized treatment extended survival to over 5 years. Interestingly, the case displayed a favorable response to immune checkpoint inhibition after acquiring mismatch repair deficiency., Conclusions: Our study demonstrates the importance of longitudinal genomic profiling to adjust to the dynamic nature of treatment-induced molecular changes to improve the outcomes of precision therapies.
- Published
- 2017
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- View/download PDF
33. Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas.
- Author
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Clark VE, Harmancı AS, Bai H, Youngblood MW, Lee TI, Baranoski JF, Ercan-Sencicek AG, Abraham BJ, Weintraub AS, Hnisz D, Simon M, Krischek B, Erson-Omay EZ, Henegariu O, Carrión-Grant G, Mishra-Gorur K, Durán D, Goldmann JE, Schramm J, Goldbrunner R, Piepmeier JM, Vortmeyer AO, Günel JM, Bilgüvar K, Yasuno K, Young RA, and Günel M
- Subjects
- Catalytic Domain genetics, Chromosomes, Human, Pair 22, Cohort Studies, DNA Mutational Analysis, Enhancer Elements, Genetic, Exome, Gene Expression Regulation, Neoplastic, Genotype, Humans, Kruppel-Like Factor 4, Kruppel-Like Transcription Factors genetics, Meningeal Neoplasms classification, Meningioma classification, Neurofibromin 2 genetics, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins genetics, Meningeal Neoplasms genetics, Meningioma genetics, Mutation, RNA Polymerase II genetics
- Abstract
RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II (ref. 1), hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors show dysregulation of key meningeal identity genes, including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO, we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features., Competing Interests: Partial funding for sequencing of the tumor samples was provided through a research agreement between Gilead Sciences, Inc., and Yale University.
- Published
- 2016
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34. A patient with a novel homozygous missense mutation in FTO and concomitant nonsense mutation in CETP.
- Author
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Çağlayan AO, Tüysüz B, Coşkun S, Quon J, Harmancı AS, Baranoski JF, Baran B, Erson-Omay EZ, Henegariu O, Mane SM, Bilgüvar K, Yasuno K, and Günel M
- Subjects
- Apoptosis genetics, Biopsy, Child, Preschool, Computational Biology methods, Consanguinity, DNA Copy Number Variations, DNA Mutational Analysis, Exome, Female, Gene Expression, Gene Expression Profiling, Genotype, High-Throughput Nucleotide Sequencing, Humans, Phenotype, Transcriptome, Alpha-Ketoglutarate-Dependent Dioxygenase FTO genetics, Cholesterol Ester Transfer Proteins genetics, Genetic Association Studies, Homozygote, Mutation, Missense
- Abstract
The fat mass and obesity associated (FTO) gene has previously been associated with a variety of diseases and conditions, notably obesity, acute coronary syndrome and metabolic syndrome. Reports describing mutations in FTO as well as in FTO animal models have further demonstrated a role for FTO in the development of the brain and other organs. Here, we describe a patient born of consanguineous union who presented with microcephaly, developmental delay, behavioral abnormalities, dysmorphic facial features, hypotonia and other various phenotypic abnormalities. Whole-exome sequencing revealed a novel homozygous missense mutation in FTO and a nonsense mutation in the cholesteryl ester transfer protein (CETP). Exome copy number variation analysis revealed no disease-causing large duplications or deletions within coding regions. Patient's, her parents' and non-related control' fibroblasts were analyzed for morphologic defects, abnormal proliferation, apoptosis and transcriptome profile. We have shown that FTO is located in the nucleus of cells from each tested sample. Western blot analysis demonstrated no changes in patient FTO. Quantitative (qPCR) analysis revealed slightly decreased levels of FTO expression in patient cells compared with controls. No morphological or proliferation differences between the patient and control fibroblasts were observed. There is still much to be learned about the molecular mechanisms by which mutations in FTO contribute to such severe phenotypes.
- Published
- 2016
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35. The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation.
- Author
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Chae WJ, Ehrlich AK, Chan PY, Teixeira AM, Henegariu O, Hao L, Shin JH, Park JH, Tang WH, Kim ST, Maher SE, Goldsmith-Pestana K, Shan P, Hwa J, Lee PJ, Krause DS, Rothlin CV, McMahon-Pratt D, and Bothwell AL
- Subjects
- Animals, Antigens, Dermatophagoides immunology, Antigens, Protozoan immunology, Cell Differentiation, Cells, Cultured, Cytokines metabolism, Extracellular Signal-Regulated MAP Kinases metabolism, Gene Expression Regulation, Humans, Inflammation immunology, Intercellular Signaling Peptides and Proteins genetics, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Models, Animal, Pyroglyphidae, Signal Transduction genetics, TOR Serine-Threonine Kinases metabolism, Asthma immunology, Blood Platelets immunology, Intercellular Signaling Peptides and Proteins metabolism, Leishmania major immunology, Leishmaniasis, Cutaneous immunology, Th2 Cells immunology, Wnt Proteins antagonists & inhibitors
- Abstract
Exposure to a plethora of environmental challenges commonly triggers pathological type 2 cell-mediated inflammation. Here we report the pathological role of the Wnt antagonist Dickkopf-1 (Dkk-1) upon allergen challenge or non-healing parasitic infection. The increased circulating amounts of Dkk-1 polarized T cells to T helper 2 (Th2) cells, stimulating a marked simultaneous induction of the transcription factors c-Maf and Gata-3, mediated by the kinases p38 MAPK and SGK-1, resulting in Th2 cell cytokine production. Circulating Dkk-1 was primarily from platelets, and the increase of Dkk-1 resulted in formation of leukocyte-platelet aggregates (LPA) that facilitated leukocyte infiltration to the affected tissue. Functional inhibition of Dkk-1 impaired Th2 cell cytokine production and leukocyte infiltration, protecting mice from house dust mite (HDM)-induced asthma or Leishmania major infection. These results highlight that Dkk-1 from thrombocytes is an important regulator of leukocyte infiltration and polarization of immune responses in pathological type 2 cell-mediated inflammation., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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- View/download PDF
36. Integrated genomic characterization of IDH1-mutant glioma malignant progression.
- Author
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Bai H, Harmancı AS, Erson-Omay EZ, Li J, Coşkun S, Simon M, Krischek B, Özduman K, Omay SB, Sorensen EA, Turcan Ş, Bakırcığlu M, Carrión-Grant G, Murray PB, Clark VE, Ercan-Sencicek AG, Knight J, Sencar L, Altınok S, Kaulen LD, Gülez B, Timmer M, Schramm J, Mishra-Gorur K, Henegariu O, Moliterno J, Louvi A, Chan TA, Tannheimer SL, Pamir MN, Vortmeyer AO, Bilguvar K, Yasuno K, and Günel M
- Subjects
- Central Nervous System Neoplasms pathology, DNA Methylation, Embryonic Stem Cells metabolism, Forkhead Box Protein M1, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism, Gene Dosage, Gene Expression Regulation, Neoplastic, Genes, myc, Glioma pathology, Humans, Isocitrate Dehydrogenase metabolism, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases metabolism, Receptor, Notch1 genetics, Receptor, Notch1 metabolism, Central Nervous System Neoplasms genetics, Glioma genetics, Isocitrate Dehydrogenase genetics, Mutation
- Abstract
Gliomas represent approximately 30% of all central nervous system tumors and 80% of malignant brain tumors. To understand the molecular mechanisms underlying the malignant progression of low-grade gliomas with mutations in IDH1 (encoding isocitrate dehydrogenase 1), we studied paired tumor samples from 41 patients, comparing higher-grade, progressed samples to their lower-grade counterparts. Integrated genomic analyses, including whole-exome sequencing and copy number, gene expression and DNA methylation profiling, demonstrated nonlinear clonal expansion of the original tumors and identified oncogenic pathways driving progression. These include activation of the MYC and RTK-RAS-PI3K pathways and upregulation of the FOXM1- and E2F2-mediated cell cycle transitions, as well as epigenetic silencing of developmental transcription factor genes bound by Polycomb repressive complex 2 in human embryonic stem cells. Our results not only provide mechanistic insight into the genetic and epigenetic mechanisms driving glioma progression but also identify inhibition of the bromodomain and extraterminal (BET) family as a potential therapeutic approach.
- Published
- 2016
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37. Mutations in KATNB1 Cause Complex Cerebral Malformations by Disrupting Asymmetrically Dividing Neural Progenitors.
- Author
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Mishra-Gorur K, Çağlayan AO, Schaffer AE, Chabu C, Henegariu O, Vonhoff F, Akgümüş GT, Nishimura S, Han W, Tu S, Baran B, Gümüş H, Dilber C, Zaki MS, Hossni HAA, Rivière JB, Kayserili H, Spencer EG, Rosti RÖ, Schroth J, Per H, Çağlar C, Çağlar Ç, Dölen D, Baranoski JF, Kumandaş S, Minja FJ, Erson-Omay EZ, Mane SM, Lifton RP, Xu T, Keshishian H, Dobyns WB, Chi NC, Šestan N, Louvi A, Bilgüvar K, Yasuno K, Gleeson JG, and Günel M
- Published
- 2015
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- View/download PDF
38. Mutations in KATNB1 cause complex cerebral malformations by disrupting asymmetrically dividing neural progenitors.
- Author
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Mishra-Gorur K, Çağlayan AO, Schaffer AE, Chabu C, Henegariu O, Vonhoff F, Akgümüş GT, Nishimura S, Han W, Tu S, Baran B, Gümüş H, Dilber C, Zaki MS, Hossni HA, Rivière JB, Kayserili H, Spencer EG, Rosti RÖ, Schroth J, Per H, Çağlar C, Çağlar Ç, Dölen D, Baranoski JF, Kumandaş S, Minja FJ, Erson-Omay EZ, Mane SM, Lifton RP, Xu T, Keshishian H, Dobyns WB, Chi NC, Šestan N, Louvi A, Bilgüvar K, Yasuno K, Gleeson JG, and Günel M
- Subjects
- Animals, Brain growth & development, Cell Count, Cell Division genetics, Dendrites genetics, Drosophila, Drosophila Proteins genetics, Humans, Katanin, Mice, Microcephaly pathology, Microtubule-Associated Proteins genetics, Mutation, Spindle Apparatus genetics, Zebrafish, Adenosine Triphosphatases genetics, Brain abnormalities, Brain pathology, Microcephaly genetics, Neural Stem Cells pathology, Neurogenesis genetics, Optic Lobe, Nonmammalian abnormalities
- Abstract
Exome sequencing analysis of over 2,000 children with complex malformations of cortical development identified five independent (four homozygous and one compound heterozygous) deleterious mutations in KATNB1, encoding the regulatory subunit of the microtubule-severing enzyme Katanin. Mitotic spindle formation is defective in patient-derived fibroblasts, a consequence of disrupted interactions of mutant KATNB1 with KATNA1, the catalytic subunit of Katanin, and other microtubule-associated proteins. Loss of KATNB1 orthologs in zebrafish (katnb1) and flies (kat80) results in microcephaly, recapitulating the human phenotype. In the developing Drosophila optic lobe, kat80 loss specifically affects the asymmetrically dividing neuroblasts, which display supernumerary centrosomes and spindle abnormalities during mitosis, leading to cell cycle progression delays and reduced cell numbers. Furthermore, kat80 depletion results in dendritic arborization defects in sensory and motor neurons, affecting neural architecture. Taken together, we provide insight into the mechanisms by which KATNB1 mutations cause human cerebral cortical malformations, demonstrating its fundamental role during brain development., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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39. The receptor for advanced glycation end products (RAGE) affects T cell differentiation in OVA induced asthma.
- Author
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Akirav EM, Henegariu O, Preston-Hurlburt P, Schmidt AM, Clynes R, and Herold KC
- Subjects
- Animals, Asthma genetics, Cell Differentiation genetics, Cell Differentiation physiology, Female, Interferon-gamma metabolism, Interleukin-17 metabolism, Interleukin-5 metabolism, Mice, Receptor for Advanced Glycation End Products, Receptors, Immunologic genetics, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets metabolism, Th2 Cells cytology, Th2 Cells metabolism, Asthma chemically induced, Asthma metabolism, Ovalbumin toxicity, Receptors, Immunologic metabolism
- Abstract
The receptor for glycation end products (RAGE) has been previously implicated in shaping the adaptive immune response. RAGE is expressed in T cells after activation and constitutively in T cells from patients with diabetes. The effects of RAGE on adaptive immune responses are not clear: Previous reports show that RAGE blockade affects Th1 responses. To clarify the role of RAGE in adaptive immune responses and the mechanisms of its effects, we examined whether RAGE plays a role in T cell activation in a Th2 response involving ovalbumin (OVA)-induced asthma in mice. WT and RAGE deficient wild-type and OT-II mice, expressing a T cell receptor specific for OVA, were immunized intranasally with OVA. Lung cellular infiltration and T cell responses were analyzed by immunostaining, FACS, and multiplex bead analyses for cytokines. RAGE deficient mice showed reduced cellular infiltration in the bronchial alveolar lavage fluid and impaired T cell activation in the mediastinal lymph nodes when compared with WT mice. In addition, RAGE deficiency resulted in reduced OT-II T cell infiltration of the lung and impaired IFNγ and IL-5 production when compared with WT mice and reduced infiltration when transferred into WT hosts. When cultured under conditions favoring the differentiation of T cells subsets, RAGE deficient T cells showed reduced production of IFNγ but increased production of IL-17. Our data show a stimulatory role for RAGE in T activation in OVA-induced asthma. This role is largely mediated by the effects of RAGE on T cell proliferation and differentiation. These findings suggest that RAGE may play a regulatory role in T cell responses following immune activation.
- Published
- 2014
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- View/download PDF
40. Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.
- Author
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Clark VE, Erson-Omay EZ, Serin A, Yin J, Cotney J, Ozduman K, Avşar T, Li J, Murray PB, Henegariu O, Yilmaz S, Günel JM, Carrión-Grant G, Yilmaz B, Grady C, Tanrikulu B, Bakircioğlu M, Kaymakçalan H, Caglayan AO, Sencar L, Ceyhun E, Atik AF, Bayri Y, Bai H, Kolb LE, Hebert RM, Omay SB, Mishra-Gorur K, Choi M, Overton JD, Holland EC, Mane S, State MW, Bilgüvar K, Baehring JM, Gutin PH, Piepmeier JM, Vortmeyer A, Brennan CW, Pamir MN, Kiliç T, Lifton RP, Noonan JP, Yasuno K, and Günel M
- Subjects
- Adult, Aged, Aged, 80 and over, Brain Neoplasms classification, Brain Neoplasms pathology, Chromosomes, Human, Pair 22 genetics, DNA Mutational Analysis, Female, Genes, Neurofibromatosis 2, Genomic Instability, Genomics, Humans, Kruppel-Like Factor 4, Male, Meningeal Neoplasms classification, Meningeal Neoplasms pathology, Meningioma classification, Meningioma pathology, Middle Aged, Mutation, Neoplasm Grading, Smoothened Receptor, Brain Neoplasms genetics, Kruppel-Like Transcription Factors genetics, Meningeal Neoplasms genetics, Meningioma genetics, Proto-Oncogene Proteins c-akt genetics, Receptors, G-Protein-Coupled genetics, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins genetics
- Abstract
We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.
- Published
- 2013
- Full Text
- View/download PDF
41. Anti-serpin antibody-mediated regulation of proteases in autoimmune diabetes.
- Author
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Baldzizhar R, Fedorchuk C, Jha M, Rathinam C, Henegariu O, and Czyzyk J
- Subjects
- Animals, Antibodies, Monoclonal therapeutic use, Antibodies, Neutralizing therapeutic use, Antigens, CD19 genetics, Antigens, CD19 immunology, CD4 Antigens genetics, CD4 Antigens immunology, Cysteine Proteinase Inhibitors pharmacology, Diabetes Mellitus, Experimental genetics, Diabetes Mellitus, Experimental immunology, Diabetes Mellitus, Type 1 genetics, Diabetes Mellitus, Type 1 immunology, Disease Progression, Female, Gene Expression, Immunity, Humoral drug effects, Interferon-gamma biosynthesis, Interferon-gamma immunology, Islets of Langerhans drug effects, Islets of Langerhans immunology, Leucine analogs & derivatives, Leucine pharmacology, Lymph Nodes drug effects, Lymph Nodes immunology, Mice, Mice, Inbred NOD, Serpins immunology, T-Lymphocytes drug effects, T-Lymphocytes immunology, Antibodies, Monoclonal pharmacology, Antibodies, Neutralizing pharmacology, Autoantibodies biosynthesis, Diabetes Mellitus, Experimental drug therapy, Diabetes Mellitus, Type 1 drug therapy, Serpins genetics
- Abstract
Secretion of anti-serpin B13 autoantibodies in young diabetes-prone nonobese diabetic mice is associated with reduced inflammation in pancreatic islets and a slower progression to autoimmune diabetes. Injection of these mice with a monoclonal antibody (mAb) against serpin B13 also leads to fewer inflammatory cells in the islets and more rapid recovery from recent-onset diabetes. The exact mechanism by which anti-serpin activity is protective remains unclear. We found that serpin B13 is expressed in the exocrine component of the mouse pancreas, including the ductal cells. We also found that anti-serpin B13 mAb blocked the inhibitory activity of serpin B13, thereby allowing partial preservation of the function of its target protease. Consistent with the hypothesis that anti-clade B serpin activity blocks the serpin from binding, exposure to exogenous anti-serpin B13 mAb or endogenous anti-serpin B13 autoantibodies resulted in cleavage of the surface molecules CD4 and CD19 in lymphocytes that accumulated in the pancreatic islets and pancreatic lymph nodes but not in the inguinal lymph nodes. This cleavage was inhibited by an E64 protease inhibitor. Consequently, T cells with the truncated form of CD4 secreted reduced levels of interferon-γ. We conclude that anti-serpin antibodies prevent serpin B13 from neutralizing proteases, thereby impairing leukocyte function and reducing the severity of autoimmune inflammation.
- Published
- 2013
- Full Text
- View/download PDF
42. Enhanced anti-serpin antibody activity inhibits autoimmune inflammation in type 1 diabetes.
- Author
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Czyzyk J, Henegariu O, Preston-Hurlburt P, Baldzizhar R, Fedorchuk C, Esplugues E, Bottomly K, Gorus FK, Herold K, and Flavell RA
- Subjects
- Adolescent, Animals, Blotting, Western, Child, Child, Preschool, Humans, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, SCID, Transfection, Young Adult, Autoantibodies immunology, Autoantigens immunology, Diabetes Mellitus, Type 1 immunology, Serpins immunology
- Abstract
Intracellular (clade B) OVA-serpin protease inhibitors play an important role in tissue homeostasis by protecting cells from death in response to hypo-osmotic stress, heat shock, and other stimuli. It is not known whether these serpins influence immunological tolerance and the risk for autoimmune diseases. We found that a fraction of young autoimmune diabetes-prone NOD mice had elevated levels of autoantibodies against a member of clade B family known as serpinB13. High levels of anti-serpinB13 Abs were accompanied by low levels of anti-insulin autoantibodies, reduced numbers of islet-associated T cells, and delayed onset of diabetes. Exposure to anti-serpinB13 mAb alone also decreased islet inflammation, and coadministration of this reagent and a suboptimal dose of anti-CD3 mAb accelerated recovery from diabetes. In a fashion similar to that discovered in the NOD model, a deficiency in humoral activity against serpinB13 was associated with early onset of human type 1 diabetes. These findings suggest that, in addition to limiting exposure to proteases within the cell, clade B serpins help to maintain homeostasis by inducing protective humoral immunity.
- Published
- 2012
- Full Text
- View/download PDF
43. Teplizumab induces human gut-tropic regulatory cells in humanized mice and patients.
- Author
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Waldron-Lynch F, Henegariu O, Deng S, Preston-Hurlburt P, Tooley J, Flavell R, and Herold KC
- Subjects
- Animals, Antibodies, Monoclonal, Humanized therapeutic use, CD3 Complex immunology, Cell Movement drug effects, Diabetes Mellitus, Type 1 drug therapy, Diabetes Mellitus, Type 1 immunology, Forkhead Transcription Factors metabolism, Gastrointestinal Tract drug effects, Humans, Hypoglycemic Agents pharmacology, Hypoglycemic Agents therapeutic use, Interleukin-10 metabolism, Intestine, Small cytology, Intestine, Small drug effects, Intestine, Small immunology, L-Selectin metabolism, Mice, Mucous Membrane cytology, Mucous Membrane drug effects, Mucous Membrane immunology, Natalizumab, Oligonucleotide Array Sequence Analysis, Receptors, CCR6 metabolism, Antibodies, Monoclonal, Humanized pharmacology, Gastrointestinal Tract cytology, Gastrointestinal Tract immunology, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory immunology
- Abstract
The development and optimization of immune therapies in patients has been hampered by the lack of preclinical models in which their effects on human immune cells can be studied. As a result, observations that have been made in preclinical studies have suggested mechanisms of drug action in murine models that have not been confirmed in clinical studies. Here, we used a humanized mouse reconstituted with human hematopoietic stem cells to study the mechanism of action of teplizumab, an Fc receptor nonbinding humanized monoclonal antibody to CD3 being tested in clinical trials for the treatment of patients with type 1 diabetes mellitus. In this model, human gut-tropic CCR6(+) T cells exited the circulation and secondary lymph organs and migrated to the small intestine. These cells then produced interleukin-10 (IL-10), a regulatory cytokine, in quantities that could be detected in the peripheral circulation. Blocking T cell migration to the small intestine with natalizumab, which prevents cellular adhesion by inhibiting α(4) integrin binding, abolished the treatment effects of teplizumab. Moreover, IL-10 expression by CD4(+)CD25(high)CCR6(+)FoxP3 cells returning to the peripheral circulation was increased in patients with type 1 diabetes treated with teplizumab. These findings demonstrate that humanized mice may be used to identify novel immunologic mechanisms that occur in patients treated with immunomodulators.
- Published
- 2012
- Full Text
- View/download PDF
44. RAGE expression in human T cells: a link between environmental factors and adaptive immune responses.
- Author
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Akirav EM, Preston-Hurlburt P, Garyu J, Henegariu O, Clynes R, Schmidt AM, and Herold KC
- Subjects
- Antigen-Presenting Cells immunology, Antigen-Presenting Cells metabolism, Bystander Effect, Diabetes Mellitus blood, Endosomes metabolism, Gene Expression Regulation, Glucose metabolism, HEK293 Cells, Humans, Interleukin-17 immunology, Interleukin-17 metabolism, Jurkat Cells, Ligands, Lymphocyte Activation, Receptor for Advanced Glycation End Products blood, Receptor for Advanced Glycation End Products genetics, Receptors, Antigen, T-Cell immunology, Receptors, Antigen, T-Cell metabolism, T-Lymphocytes metabolism, Adaptive Immunity, Diabetes Mellitus immunology, Receptor for Advanced Glycation End Products immunology, T-Lymphocytes immunology
- Abstract
The Receptor for Advanced Glycation Endproducts (RAGE) is a scavenger ligand that binds glycated endproducts as well as molecules released during cell death such as S100b and HMGB1. RAGE is expressed on antigen presenting cells where it may participate in activation of innate immune responses but its role in adaptive human immune responses has not been described. We have found that RAGE is expressed intracellularly in human T cells following TCR activation but constitutively on T cells from patients with diabetes. The levels of RAGE on T cells from patients with diabetes are not related to the level of glucose control. It co-localizes to the endosomes. Its expression increases in activated T cells from healthy control subjects but bystander cells also express RAGE after stimulation of the antigen specific T cells. RAGE ligands enhance RAGE expression. In patients with T1D, the level of RAGE expression decreases with T cell activation. RAGE+ T cells express higher levels of IL-17A, CD107a, and IL-5 than RAGE- cells from the same individual with T1D. Our studies have identified the expression of RAGE on adaptive immune cells and a role for this receptor and its ligands in modulating human immune responses.
- Published
- 2012
- Full Text
- View/download PDF
45. Detection of β cell death in diabetes using differentially methylated circulating DNA.
- Author
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Akirav EM, Lebastchi J, Galvan EM, Henegariu O, Akirav M, Ablamunits V, Lizardi PM, and Herold KC
- Subjects
- Animals, Base Sequence, Cloning, Molecular, DNA genetics, DNA Primers genetics, Diabetes Mellitus blood, Female, Fluorescent Antibody Technique, Humans, Insulin-Secreting Cells chemistry, Mice, Mice, Inbred BALB C, Mice, Inbred NOD, Molecular Sequence Data, Monitoring, Physiologic methods, Real-Time Polymerase Chain Reaction, Sequence Analysis, DNA, Cell Death physiology, DNA blood, Diabetes Mellitus pathology, Insulin genetics, Insulin-Secreting Cells pathology
- Abstract
In diabetes mellitus, β cell destruction is largely silent and can be detected only after significant loss of insulin secretion capacity. We have developed a method for detecting β cell death in vivo by amplifying and measuring the proportion of insulin 1 DNA from β cells in the serum. By using primers that are specific for DNA methylation patterns in β cells, we have detected circulating copies of β cell-derived demethylated DNA in serum of mice by quantitative PCR. Accordingly, we have identified a relative increase of β cell-derived DNA after induction of diabetes with streptozotocin and during development of diabetes in nonobese diabetic mice. We have extended the use of this assay to measure β cell-derived insulin DNA in human tissues and serum. We found increased levels of demethylated insulin DNA in subjects with new-onset type 1 diabetes compared with age-matched control subjects. Our method provides a noninvasive approach for detecting β cell death in vivo that may be used to track the progression of diabetes and guide its treatment.
- Published
- 2011
- Full Text
- View/download PDF
46. NKG2A is a marker for acquisition of regulatory function by human CD8+ T cells activated with anti-CD3 antibody.
- Author
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Ablamunits V, Henegariu O, Preston-Hurlburt P, and Herold KC
- Subjects
- Biomarkers, Gene Expression, Humans, Interleukin-2 Receptor alpha Subunit analysis, Lymphocyte Activation, Microarray Analysis, NK Cell Lectin-Like Receptor Subfamily C agonists, NK Cell Lectin-Like Receptor Subfamily C immunology, NK Cell Lectin-Like Receptor Subfamily C metabolism, Polymerase Chain Reaction, Protein Isoforms, Receptors, Tumor Necrosis Factor, Type II analysis, Antibodies, Monoclonal immunology, CD3 Complex immunology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, NK Cell Lectin-Like Receptor Subfamily C genetics, T-Lymphocytes, Regulatory immunology
- Abstract
Treatment with anti-CD3 mAb modulates immune responses that cause type 1 diabetes and other diseases. CD8+ Tregs can be induced in vitro and in vivo by mAb. However, 1/3 of patients do not respond to drug therapy and in an equal proportion, anti-CD3 mAb does not induce Tregs in vitro. The acquisition of CD8+ Treg activity is a function of the CD8+ cells and not the targets in the assay. To identify markers to differentiate responses of CD8+ Tregs, we analyzed genes differentially expressed in CD8+ T cells of non-responders compared with responders, and found that an inhibitory receptor NKG2A (CD159a) was highly expressed in cells from all non-responders tested. Application of a mAb agonistic to NKG2A during in vitro CD8+ Treg induction by anti-CD3 prevented induction of CD8+ Tregs. CD8+ T cells that are TNFR2+ but NKG2A- are the most potently induced Tregs. The level of NKG2A expression on resting CD8+ T cells inversely correlated with acquisition of regulatory function when activated. We suggest that the induction of human CD8+ Tregs by anti-CD3 mAb is controlled by a negative signaling through NKG2A, and that NKG2A may serve as a negative marker of human CD8+ Tregs., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2011
- Full Text
- View/download PDF
47. Elevated expression of MCP-1, IL-2 and PTPR-N in basal ganglia of Tourette syndrome cases.
- Author
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Morer A, Chae W, Henegariu O, Bothwell AL, Leckman JF, and Kawikova I
- Subjects
- Adult, Aged, Autopsy, Basal Ganglia metabolism, Chemokine CCL2 genetics, Female, Humans, Interferon-gamma genetics, Interferon-gamma immunology, Interleukin-1beta genetics, Interleukin-1beta immunology, Interleukin-2 genetics, Leukocyte Common Antigens genetics, Leukocyte Common Antigens immunology, Male, Middle Aged, Polymerase Chain Reaction, RNA, Receptor-Like Protein Tyrosine Phosphatases, Class 2 genetics, Receptor-Like Protein Tyrosine Phosphatases, Class 2 immunology, Receptor-Like Protein Tyrosine Phosphatases, Class 8 genetics, Recoverin genetics, Recoverin immunology, Tourette Syndrome genetics, Basal Ganglia immunology, Chemokine CCL2 immunology, Interleukin-2 immunology, Receptor-Like Protein Tyrosine Phosphatases, Class 8 immunology, Tourette Syndrome immunology
- Abstract
Background: Post-infectious autoimmunity has been implicated in pathogenesis of Tourette's syndrome (TS) but no evidence of inflammation in central nervous system has been reported yet. We evaluated the expression of genes encoding selected inflammatory factors in post-mortem specimen of adult TS patients: interferon-γ (a cytokine released from CD8 and Thelper 1 CD4 subset of T lymphocytes), interleukin-2 (IL-2, a growth factor derived from T lymphocytes), interleukin-1 β (a cytokine involved in initiation of inflammation), monocyte chemotactic factor -1 (MCP-1, a marker of chronic inflammation) and CD45 (pan-leukocytic marker). For validation purposes, we determined expression of three genes that were previously reported to be elevated in post-mortem specimen of other TS cases: protein tyrosine phosphatase receptor-N (PTPR-N), PTPR-U and recoverin., Methods: Total RNA was isolated from formalin fixed brain tissue sections of basal ganglia area from four patients with TS and four control subjects, and real-time reverse transcription-polymerase chain reaction analysis was employed to quantitatively evaluate gene expression of the selected genes., Results: Significantly increased expression of MCP-1, IL-2 and PTPR-N was observed in TS cases (6.5-fold, 2.3-fold and 16.1-fold increase, respectively, p<0.05)., Conclusions: Elevated expression of MCP-1 and IL-2 supports the possibility of chronic inflammatory processes in the basal ganglia. Replication of elevated expression of PTPR-N in TS specimen suggests that pathway(s) involving this molecule may be important in TS pathogenesis., (Copyright © 2010 Elsevier Inc. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
48. Ablation of IL-17A abrogates progression of spontaneous intestinal tumorigenesis.
- Author
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Chae WJ, Gibson TF, Zelterman D, Hao L, Henegariu O, and Bothwell AL
- Subjects
- Animals, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes pathology, Cytokines genetics, Genes, APC, Inflammation Mediators metabolism, Interleukin-17 genetics, Interleukin-17 physiology, Intestinal Neoplasms genetics, Intestinal Neoplasms pathology, Lymphocytes, Tumor-Infiltrating immunology, Lymphocytes, Tumor-Infiltrating pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Mutant Strains, Phenotype, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Neoplasm genetics, RNA, Neoplasm metabolism, Spleen immunology, Spleen pathology, Thymus Gland immunology, Thymus Gland pathology, Interleukin-17 deficiency, Intestinal Neoplasms etiology, Intestinal Neoplasms immunology
- Abstract
The intrinsic role of endogenous IL-17A in spontaneous intestinal tumorigenesis has not been addressed previously to our knowledge. Ablation of IL-17A significantly reduced tumor development in mice bearing a heterozygote mutation in the adenomatous polyposis coli (APC) gene (Apc(Min/+) mice). There was also a decrease in inflammatory cytokines and proinflammatory mediators, reduced infiltration of lymphocytes including T cells, and preservation of intestinal architecture and the presence of APC protein in intestinal epithelial cells. Interestingly, IL-17A ablation also corrected immunological abnormalities such as splenomegaly and thymic atrophy in Apc(Min/+) mice. CD4 T cells from Apc(Min/+) mice showed hyperproliferative potential in vitro and in vivo and increased levels of IL-17A and IL-10. The effector CD4 T cells from Apc(Min/+) mice were more resistant to regulatory T cell-mediated suppression. Finally, these CD4 T cells induced colitis in immunodeficient mice upon adoptive transfer, whereas the ablation of IL-17A in CD4 T cells in Apc(Min/+) mice completely abolished this pathogenic potential in vivo. Taken together, our results show that CD4 T cell-derived IL-17A promotes spontaneous intestinal tumorigenesis with altered functions of CD4 T cells in Apc(Min/+) mice.
- Published
- 2010
- Full Text
- View/download PDF
49. Inflammatory regulation by TLR3 in acute hepatitis.
- Author
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Xiao X, Zhao P, Rodriguez-Pinto D, Qi D, Henegariu O, Alexopoulou L, Flavell RA, Wong FS, and Wen L
- Subjects
- Acute Disease, Animals, Chemical and Drug Induced Liver Injury etiology, Concanavalin A, Gene Expression Regulation, Hematopoietic Stem Cells metabolism, Hematopoietic Stem Cells pathology, Hepatocytes pathology, Liver metabolism, Liver pathology, Mice, T-Lymphocytes immunology, Toll-Like Receptor 3 administration & dosage, Toll-Like Receptor 3 deficiency, Toll-Like Receptor 3 genetics, Chemical and Drug Induced Liver Injury pathology, Inflammation etiology, Toll-Like Receptor 3 physiology
- Abstract
TLR3 is known to respond to dsRNA from viruses, apoptotic cells, and/or necrotic cells. Dying cells are a rich source of ligands that can activate TLRs, such as TLR3. TLR3 expressed in the liver is likely to be a mediator of innate activation and inflammation in the liver. The importance of this function of TLR3 during acute hepatitis has not previously been fully explored. We used the mouse model of Con A-induced hepatitis and observed a novel role for TLR3 in hepatocyte damage in the absence of an exogenous viral stimulus. Interestingly, TLR3 expression in liver mononuclear cells and sinus endothelial cells was up-regulated after Con A injection and TLR3(-/-) mice were protected from Con A-induced hepatitis. Moreover, splenocytes from TLR3(-/-) mice proliferated less to Con A stimulation in the presence of RNA derived from damaged liver tissue compared with wild-type (WT) mice. To determine the relative contribution of TLR3 expression by hematopoietic cells or nonhematopoietic to liver damage during Con A-induced hepatitis, we generated bone marrow chimeric mice. TLR3(-/-) mice engrafted with WT hematopoietic cells were protected in a similar manner to WT mice reconstituted with TLR3(-/-) bone marrow, indicating that TLR3 signaling in both nonhematopoietic and hematopoietic cells plays an important role in mediating liver damage. In summary, our data suggest that TLR3 signaling is necessary for Con A-induced liver damage in vivo and that TLR3 regulates inflammation and the adaptive T cell immune response in the absence of viral infection.
- Published
- 2009
- Full Text
- View/download PDF
50. RAGE ligation affects T cell activation and controls T cell differentiation.
- Author
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Chen Y, Akirav EM, Chen W, Henegariu O, Moser B, Desai D, Shen JM, Webster JC, Andrews RC, Mjalli AM, Rothlein R, Schmidt AM, Clynes R, and Herold KC
- Subjects
- Animals, Cell Differentiation genetics, Cell Proliferation, Cells, Cultured, Diabetes Mellitus, Type 1 enzymology, Diabetes Mellitus, Type 1 genetics, Diabetes Mellitus, Type 1 immunology, Glycation End Products, Advanced metabolism, Graft Survival drug effects, Graft Survival immunology, Islets of Langerhans Transplantation immunology, Islets of Langerhans Transplantation pathology, Ligands, Lymphocyte Activation genetics, Lymphocyte Culture Test, Mixed, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Mice, Transgenic, Receptor for Advanced Glycation End Products, Receptors, Immunologic antagonists & inhibitors, Receptors, Immunologic deficiency, Receptors, Immunologic genetics, T-Lymphocyte Subsets pathology, Th1 Cells enzymology, Th1 Cells immunology, Th1 Cells pathology, Th2 Cells enzymology, Th2 Cells immunology, Th2 Cells pathology, Cell Differentiation immunology, Lymphocyte Activation immunology, Receptors, Immunologic metabolism, T-Lymphocyte Subsets enzymology, T-Lymphocyte Subsets immunology
- Abstract
The pattern recognition receptor, RAGE, has been shown to be involved in adaptive immune responses but its role on the components of these responses is not well understood. We have studied the effects of a small molecule inhibitor of RAGE and the deletion of the receptor (RAGE-/- mice) on T cell responses involved in autoimmunity and allograft rejection. Syngeneic islet graft and islet allograft rejection was reduced in NOD and B6 mice treated with TTP488, a small molecule RAGE inhibitor (p < 0.001). RAGE-/- mice with streptozotocin-induced diabetes showed delayed rejection of islet allografts compared with wild type (WT) mice (p < 0.02). This response in vivo correlated with reduced proliferative responses of RAGE-/- T cells in MLRs and in WT T cells cultured with TTP488. Overall T cell proliferation following activation with anti-CD3 and anti-CD28 mAbs were similar in RAGE-/- and WT cells, but RAGE-/- T cells did not respond to costimulation with anti-CD28 mAb. Furthermore, culture supernatants from cultures with anti-CD3 and anti-CD28 mAbs showed higher levels of IL-10, IL-5, and TNF-alpha with RAGE-/- compared with WT T cells, and WT T cells showed reduced production of IFN-gamma in the presence of TTP488, suggesting that RAGE may be important in the differentiation of T cell subjects. Indeed, by real-time PCR, we found higher levels of RAGE mRNA expression on clonal T cells activated under Th1 differentiating conditions. We conclude that activation of RAGE on T cells is involved in early events that lead to differentiation of Th1(+) T cells.
- Published
- 2008
- Full Text
- View/download PDF
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