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Grazyna Kochan

Bio: Grazyna Kochan is an academic researcher from Universidad Pública de Navarra. The author has contributed to research in topics: Immunotherapy & Immune system. The author has an hindex of 28, co-authored 95 publications receiving 3439 citations. Previous affiliations of Grazyna Kochan include University of Gdańsk & University of Oxford.


Papers
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Journal ArticleDOI
David M. Evans1, Spencer Cca.2, J J Pointon3, Zhan Su2, D Harvey3, Grazyna Kochan2, Udo Oppermann4, Alexander T. Dilthey5, Matti Pirinen5, Millicent A. Stone6, L H Appleton3, Loukas Moutsianas2, Stephen Leslie2, T. W. H. Wordsworth3, Tony J. Kenna7, Tugce Karaderi3, Gethin P. Thomas7, Minghong Ward8, Michael H. Weisman9, C. Farrar3, Linda A. Bradbury7, Patrick Danoy7, Robert D. Inman10, Walter P. Maksymowych11, Dafna D. Gladman10, Proton Rahman12, Ann W. Morgan13, Helena Marzo-Ortega13, Paul Bowness3, Karl Gaffney14, Gaston Jsh.15, Malcolm D. Smith15, Jácome Bruges-Armas16, Couto A-R.17, Rosa Sorrentino17, Fabiana Paladini17, Manuel A. R. Ferreira18, Huji Xu19, Yu Liu19, L. Jiang19, Carlos López-Larrea, Roberto Díaz-Peña, Antonio López-Vázquez, Tetyana Zayats5, Céline Bellenguez2, Hannah Blackburn, Jenefer M. Blackwell20, Elvira Bramon21, Suzannah Bumpstead21, Juan P. Casas22, Aiden Corvin23, N. Craddock24, Panagiotis Deloukas21, Serge Dronov21, Audrey Duncanson25, Sarah Edkins21, Colin Freeman26, Matthew W. Gillman21, Emma Gray21, R. Gwilliam21, Naomi Hammond21, Sarah E. Hunt21, Janusz Jankowski, Alagurevathi Jayakumar21, Cordelia Langford21, Jennifer Liddle21, Hugh S. Markus27, Christopher G. Mathew28, O. T. McCann21, Mark I. McCarthy29, Palmer Cna.21, Leena Peltonen21, Robert Plomin28, Simon C. Potter21, Anna Rautanen21, Radhi Ravindrarajah21, Michelle Ricketts21, Nilesh J. Samani30, Stephen Sawcer31, A. Strange26, Richard C. Trembath28, Ananth C. Viswanathan32, Ananth C. Viswanathan33, Matthew Waller21, Paul A. Weston21, Pamela Whittaker21, Sara Widaa21, Nicholas W. Wood, Gil McVean26, John D. Reveille34, B P Wordsworth35, Matthew A. Brown35, Peter Donnelly26 
TL;DR: In this paper, the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 x 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all their datasets (p < 5x 10(-6) overall, with support in each of the three datasets studied).
Abstract: Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 x 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 x 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

798 citations

David M. Evans, C. C. A. Spencer, J J Pointon, Zhan Su, David Harvey, Grazyna Kochan, U. Opperman, Alexander T. Dilthey, Matti Pirinen, Stone, L H Appleton, L. Moutsianis, Stephen Leslie, T. W. H. Wordsworth, Tony J. Kenna, Tugce Karaderi, Gethin P. Thomas, M. M. Ward, Michael H. Weisman, C Farrar, Linda A. Bradbury, Patrick Danoy, Robert D. Inman, Walter P. Maksymowych, Dafna D. Gladman, Proton Rahman, Ann W. Morgan, Helena Marzo-Ortega, Paul Bowness, Karl Gaffney, J. S. H. Gaston, Malcolm D. Smith, Jácome Bruges-Armas, Ana Rita Couto, Rosa Sorrentino, Fabiana Paladini, Ferreira, Huji Xu, Yu Liu, L. Jiang, Carlos López-Larrea, Roberto Díaz-Peña, A. Lóepez-Vázquez, Tetyana Zayats, Céline Bellenguez, H. D. Blackburn, Jenefer M. Blackwell, Elvira Bramon, Suzannah Bumpstead, Juan P. Casas, Aiden Corvin, N. Craddock, Panagiotis Deloukas, Serge Dronov, Audrey Duncanson, Sarah Edkins, Colin Freeman, Matthew W. Gillman, Erin Gray, R. Gwilliam, Naomi Hammond, Sarah E. Hunt, Janusz Jankowski, Alagurevathi Jayakumar, Cordelia Langford, Jennifer Liddle, Hugh S. Markus, Christopher G. Mathew, O. T. McCann, Mark I. McCarthy, Colin N. A. Palmer, Leena Peltonen, Robert Plomin, Simon C. Potter, Anna Rautanen, Radhi Ravindrarajah, Michelle Ricketts, Nilesh J. Samani, Stephen Sawcer, A. Strange, Richard C. Trembath, Ananth C. Viswanathan, Matthew Waller, Paul A. Weston, Pamela Whittaker, Sara Widaa, Nicholas W. Wood, Gil McVean, John D. Reveille, B P Wordsworth, Brown, Peter Donnelly 
01 Jan 2011
TL;DR: This paper reported the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P -8 in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9.
Abstract: Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P -8 in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P -6 overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

255 citations

Journal ArticleDOI
05 Jul 2018-Mbio
TL;DR: Key roles for the ion channel and PBM domains in optimal virus replication and pathogenesis are demonstrated and suggest that the viral viroporins and PBMs are suitable targets for antiviral therapy and for mutation in attenuated SARS-CoV vaccines.
Abstract: Viroporins are viral proteins with ion channel (IC) activity that play an important role in several processes, including virus replication and pathogenesis. While many coronaviruses (CoVs) encode two viroporins, severe acute respiratory syndrome CoV (SARS-CoV) encodes three: proteins 3a, E, and 8a. Additionally, proteins 3a and E have a PDZ-binding motif (PBM), which can potentially bind over 400 cellular proteins which contain a PDZ domain, making them potentially important for the control of cell function. In the present work, a comparative study of the functional motifs included within the SARS-CoV viroporins was performed, mostly focusing on the roles of the IC and PBM of E and 3a proteins. Our results showed that the full-length E and 3a proteins were required for maximal SARS-CoV replication and virulence, whereas viroporin 8a had only a minor impact on these activities. A virus missing both the E and 3a proteins was not viable, whereas the presence of either protein with a functional PBM restored virus viability. E protein IC activity and the presence of its PBM were necessary for virulence in mice. In contrast, the presence or absence of the homologous motifs in protein 3a did not influence virus pathogenicity. Therefore, dominance of the IC and PBM of protein E over those of protein 3a was demonstrated in the induction of pathogenesis in mice.IMPORTANCE Collectively, these results demonstrate key roles for the ion channel and PBM domains in optimal virus replication and pathogenesis and suggest that the viral viroporins and PBMs are suitable targets for antiviral therapy and for mutation in attenuated SARS-CoV vaccines.

241 citations

Journal ArticleDOI
TL;DR: In this paper, the authors determined crystal structures in open and closed states of human endoplasmatic reticulum aminopeptidase 1 (ERAP1), which provided the first snapshots along a catalytic path.
Abstract: Endoplasmatic reticulum aminopeptidase 1 (ERAP1) is a multifunctional enzyme involved in trimming of peptides to an optimal length for presentation by major histocompatibility complex (MHC) class I molecules. Polymorphisms in ERAP1 have been associated with chronic inflammatory diseases, including ankylosing spondylitis (AS) and psoriasis, and subsequent in vitro enzyme studies suggest distinct catalytic properties of ERAP1 variants. To understand structure-activity relationships of this enzyme we determined crystal structures in open and closed states of human ERAP1, which provide the first snapshots along a catalytic path. ERAP1 is a zinc-metallopeptidase with typical H-E-X-X-H-(X)18-E zinc binding and G-A-M-E-N motifs characteristic for members of the gluzincin protease family. The structures reveal extensive domain movements, including an active site closure as well as three different open conformations, thus providing insights into the catalytic cycle. A K528R mutant strongly associated with AS in GWAS studies shows significantly altered peptide processing characteristics, which are possibly related to impaired interdomain interactions.

239 citations

Journal ArticleDOI
TL;DR: PDL1 cell-intrinsic signaling protects cancer cells from interferon (IFN) cytotoxicity and accelerates tumor progression and reveals a mode of action of PDL1 in cancer cells as a first line of defense against IFN cytot toxicity.

195 citations


Cited by
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Journal Article
TL;DR: This volume is keyed to high resolution electron microscopy, which is a sophisticated form of structural analysis, but really morphology in a modern guise, the physical and mechanical background of the instrument and its ancillary tools are simply and well presented.
Abstract: I read this book the same weekend that the Packers took on the Rams, and the experience of the latter event, obviously, colored my judgment. Although I abhor anything that smacks of being a handbook (like, \"How to Earn a Merit Badge in Neurosurgery\") because too many volumes in biomedical science already evince a boyscout-like approach, I must confess that parts of this volume are fast, scholarly, and significant, with certain reservations. I like parts of this well-illustrated book because Dr. Sj6strand, without so stating, develops certain subjects on technique in relation to the acquisition of judgment and sophistication. And this is important! So, given that the author (like all of us) is somewhat deficient in some areas, and biased in others, the book is still valuable if the uninitiated reader swallows it in a general fashion, realizing full well that what will be required from the reader is a modulation to fit his vision, propreception, adaptation and response, and the kind of problem he is undertaking. A major deficiency of this book is revealed by comparison of its use of physics and of chemistry to provide understanding and background for the application of high resolution electron microscopy to problems in biology. Since the volume is keyed to high resolution electron microscopy, which is a sophisticated form of structural analysis, but really morphology in a modern guise, the physical and mechanical background of The instrument and its ancillary tools are simply and well presented. The potential use of chemical or cytochemical information as it relates to biological fine structure , however, is quite deficient. I wonder when even sophisticated morphol-ogists will consider fixation a reaction and not a technique; only then will the fundamentals become self-evident and predictable and this sine qua flon will become less mystical. Staining reactions (the most inadequate chapter) ought to be something more than a technique to selectively enhance contrast of morphological elements; it ought to give the structural addresses of some of the chemical residents of cell components. Is it pertinent that auto-radiography gets singled out for more complete coverage than other significant aspects of cytochemistry by a high resolution microscopist, when it has a built-in minimal error of 1,000 A in standard practice? I don't mean to blind-side (in strict football terminology) Dr. Sj6strand's efforts for what is \"routinely used in our laboratory\"; what is done is usually well done. It's just that …

3,197 citations

Journal ArticleDOI
TL;DR: The past five years have seen many scientific and biological discoveries made through the experimental design of genome-wide association studies (GWASs), which were aimed at detecting variants at genomic loci that are associated with complex traits in the population and, in particular, at detecting associations between common single-nucleotide polymorphisms (SNPs) and common diseases such as heart disease, diabetes, auto-immune diseases, and psychiatric disorders.
Abstract: The past five years have seen many scientific and biological discoveries made through the experimental design of genome-wide association studies (GWASs). These studies were aimed at detecting variants at genomic loci that are associated with complex traits in the population and, in particular, at detecting associations between common single-nucleotide polymorphisms (SNPs) and common diseases such as heart disease, diabetes, auto-immune diseases, and psychiatric disorders. We start by giving a number of quotes from scientists and journalists about perceived problems with GWASs. We will then briefly give the history of GWASs and focus on the discoveries made through this experimental design, what those discoveries tell us and do not tell us about the genetics and biology of complex traits, and what immediate utility has come out of these studies. Rather than giving an exhaustive review of all reported findings for all diseases and other complex traits, we focus on the results for auto-immune diseases and metabolic diseases. We return to the perceived failure or disappointment about GWASs in the concluding section.

2,361 citations

BookDOI
01 Jan 2011
TL;DR: Firm evidence is provided for Foxp3+CD25+CD4+ Treg cells as an indispensable cellular constituent of the normal immune system for establishing and maintaining immunologic self-tolerance and immune homeostasis.
Abstract: Despite the skepticism that once prevailed among immunologists, it is now widely accepted that the normal immune system harbors a T-cell population, called regulatory T cells (Treg cells), specialized for immune suppression. It was first shown that depletion of a T-cell subpopulation from normal rodents produced autoimmune disease. Search for a molecular marker specific for such autoimmune-preventive Treg cells has revealed that the majority, if not all, of them constitutively express the CD25 molecule as depletion of CD25+CD4+ T cells spontaneously evokes autoimmune disease in otherwise normal rodents. The expression of CD25 by Treg cells has made it possible to delineate their developmental pathways, in particular their thymic development, and establish simple in vitro assay for assessing their suppressive activity. The marker and the in vitro assay have helped to identify human Treg cells with similar functional and phenotypic characteristics. Recent efforts have shown that natural Treg cells specifically express the transcription factor Foxp3 and that mutations of the Foxp3 gene produce a variety of immunological diseases in humans and rodents. Specific expression of Foxp3 in natural Treg cells has enabled their functional and developmental characterization by genetic approach. These studies altogether have provided firm evidence for Foxp3+CD25+CD4+ Treg cells as an indispensable cellular constituent of the normal immune system for establishing and maintaining immunologic self-tolerance and immune homeostasis. Treg cells are now within the scope of clinical use to treat immunological diseases and control physiological and pathological immune responses.

1,745 citations

Journal ArticleDOI
TL;DR: A timely evaluation of the biology of antigen presentation and a survey of issues that are considered unresolved are presented.
Abstract: The molecular details of antigen processing and presentation by MHC class I and class II molecules have been studied extensively for almost three decades. Although the basic principles of these processes were laid out approximately 10 years ago, the recent years have revealed many details and provided new insights into their control and specificity. MHC molecules use various biochemical reactions to achieve successful presentation of antigenic fragments to the immune system. Here we present a timely evaluation of the biology of antigen presentation and a survey of issues that are considered unresolved. The continuing flow of new details into our understanding of the biology of MHC class I and class II antigen presentation builds a system involving several cell biological processes, which is discussed in this Review.

1,571 citations

Journal ArticleDOI
TL;DR: It is shown here that a substantial portion of missing heritability could arise from overestimation of the denominator, creating “phantom heritability,” and a method for estimating heritability from isolated populations that is not inflated by genetic interactions is described.
Abstract: justified, because models with interactions are also consistent with observable data; and (iii) under such models, the total heritability may be much smaller and thus the proportion of heritability explained much larger. For example, 80% of the currently missing heritability for Crohn’s disease could be due to genetic interactions, if the disease involves interaction among three pathways. In short, missing heritability need not directly correspond to missing variants, because current estimates of total heritability may be significantly inflated by genetic interactions. Finally, we describe a method for estimating heritability from isolated populations that is not inflated by genetic interactions.

1,505 citations