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X-Linked Genetic Factors Behind Gender Bias in Rheumatoid Arthritis

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X-Linked Genetic Factors Behind Gender Bias in Rheumatoid Arthritis SAMI-BARNA KANAAN X-LINKED GENETIC FACTORS BEHIND GENDER BIAS IN RHEUMATOID ARTHRITIS DISSERTATION DISCIPLINE: IMMUNOLOGY; SUPERVISED BY DR. NATHALIE C. LAMBERT THE DOCTORAL COLLEGE OF LIFE SCIENCE AND HEALTH (ECOLE DOCTORALE DES SCIENCES DE LA VIE ET DE LA SANTE – ED62) OF AIX MARSEILLE UNIVERSITY, FRANCE JURY: PR. JEAN ROUDIER (PRESIDENT) PR. SÉLIM ARACTINGI (REVIEWER) PR. JEAN-CHARLES GUÉRY (REVIEWER) DR. NATHALIE C. LAMBERT (SUPERVISOR) PR. PHILIPPE NAQUET (EXAMINATOR) DR. CHRISTOPHE PICARD (EXAMINATOR) MARSEILLE, FRANCE – 20TH OF DECEMBER 2013 SAMI-BARNA KANAAN FACTEURS DE RISQUE LIES AU CHROMOSOME X A L’ORIGINE DE LA PREDOMINANCE DES FEMMES DANS LA POLYARTHRITE RHUMATOÏDE THESE SOUMISE A L’ECOLE DOCTORALE DES SCIENCES DE LA VIE ET DE LA SANTE – ED62 D’AIX MARSEILLE UNIVERSITE, FRANCE POUR L’OBTENTION DU DIPLOME DE DOCTEUR D’AIX-MARSEILLE UNIVERSITE DISCIPLINE : IMMUNOLOGIE LABORATOIRE : INSERM UMRs1097 “GENES HLA-DR, AUTOANTICORPS ET MICROCHIMERISME DANS LA POLYARTHRITE RHUMATOÏDE ET LA SCLERODERMIE” DIRECTRICE DE THESE : DR. NATHALIE C. LAMBERT JURY: PR. JEAN ROUDIER (PRESIDENT) PR. SÉLIM ARACTINGI (RAPPORTEUR) PR. JEAN-CHARLES GUÉRY (RAPPORTEUR) DR. NATHALIE C. LAMBERT (DIRECTRICE) PR. PHILIPPE NAQUET (EXAMINATEUR) DR. CHRISTOPHE PICARD (EXAMINATEUR) SOUTENUE PUBLIQUEMENT LE 20 DECEMBRE 2013 – MARSEILLE, FRANCE University Address: Aix-Marseille Université Ecole doctorale des sciences de la vie et de la santé –ED62 Faculté des Sciences de Luminy, case 901, 163 avenue de Luminy, 13288 MARSEILLE cedex 09 France E-mail : [email protected] Laboratory Address: Laboratoire « Gènes HLA-DR, autoanticorps et microchimérisme dans la polyarthrite rhumatoïde et la sclérodermie » INSERM UMRs1097 Parc scientifique et technologique de Luminy, Case 939 163, avenue de Luminy Bâtiment TPR2 Inserm - Entrée A, 1er étage 13288 Marseille cedex 09 France E-mail : [email protected] ACKNOWLEDGMENTS First of all to my sweetheart Yousra who is always encouraging and supporting me in almost everything I do. She is family, along with Hajnal and Imad (my mom and dad), Ayman and Sanaa (my brother and sister) who I thank deeply, because without them, I would not have been who I am and none of this work would have seen the light. A ton of thanks to my Ph.D. supervisor Nathalie C. Lambert, always enthusiastic, always motivating. I have learned so much in these four years (3 Ph.D. and 1 Masters). Thanks to her, I have been to many places and scientific conferences in Europe. I have learned great lessons not only in immunology, but also in real life. It is hard to find another awesome supervisor like her. She inspires me to be just like her in the future! Sincere thanks to Jean Roudier, head of our laboratory, who welcomed me among his team and has been a constant source of help, advice and encouragements. I will never forget him saying, on my first day: “a researcher who never sees the United States of America is like a sailor who never sees the ocean”. Many many thanks to the entire working group. They are not just my lab-mates, they are my friends. Isabelle, for her availability, for her kindness, for her comments, all the time intelligent, always turning my work for the better. She has read my thesis in about three hours. All of it. Elisabeth for her management assistance, but mostly for her kindness. She has been the French version of a mother to me. Nathalie Balandraud for her remarks and supporting of my activities, also for recruitment of patients. Thanks to Marielle, Emmanuelle, Nicolas, Jean- Marc, Doua (my live memory, when I was inattentive), Fanny, Karlin, for all the wonderful interactions and for contributing to an excellent working environment. I need a few more theses to write pages about them all. Thanks to all the jury members for participating to my defense, and to the reviewers for accepting to evaluate my work. It is a great honor to present them my thesis. Thanks to the QKRAA association, the Group Francophone de la Recherche sur la Sclérodermie (GFRS) and Fondation Arthritis Courtin for sponsoring me through my Ph.D. Huge thanks to all my wonderful friends, old ones and new ones, for backing me up from day one, for sharing with me good times and supporting me through hard times. Thanks to Ali, Esber, Sarah, Wasim, Kifah, Abbas, Eleonore, Rabih, Hassan, Rana, Noura, and many, many others… Thank you all. DEDICATION I would like to dedicate this thesis to my future self. Hopefully, one day, I will develop my career as a scientist in immunology (or perhaps genetics of immunology), a field for which I have grown a passion over the last few years. This is due in big part to the excellent academic atmosphere in the scientific park of Luminy, at the Aix- Marseille University (France), and to the awesomeness of all the people that have had outstanding influence on me during this journey (see acknowledgements). This day, I will be sipping my coffee at my senior professor desk, and I will be thinking, as I remember this dissertation: “thank you past self, high five!” “Let us suppose you are walking along and you see lightning strike the ground, and just at the place and moment where it hits, a basketball appears out of nowhere. That would be pretty amazing, and you would probably call it a magical event. However, let us suppose that you make the same trip every day, and that every time lightning strikes a certain place, a basketball appears – that you could logically call science. Let me explain what I mean. Sometimes it would appear that the only difference between science and magic is that science repeats.” –Louis J. DeFelice (Biologist) ABSTRACT (ENGLISH) Women are at higher risk compared to men in most autoimmune diseases. Several hypotheses have been proposed to explain this gender bias. The aim of my PhD is to understand female predominance in rheumatismal autoimmune disease, with special focus on Rheumatoid Arthritis (RA) and on the X chromosome. This chromosome is of particular interest in this context as it harbors a significant number of genes with immune functions. For that purpose, we have analyzed i) the genetic and ii) epigenetic influence of the X chromosome in RA. i) Genetic influence of X-linked genes Toll-like receptor 7 (Tlr7) gene, an X-linked gene important in the innate immune system, has been reported to be essential in accelerating autoimmunity in males in an autoimmune murine model (Yaa model). We have investigated the possibility of a gene copy increase of TLR7 and its paralog TLR8 in men with RA. We present evidence that copy numbers of TLR7 and TLR8 genes significantly increase with age in peripheral blood cells of men, whether they are healthy or with RA. Importantly, this age mediated variation is not a 2-fold increase in all cells (TLR7/8 duplication) as observed in the Yaa mouse model, but rather of small amplitude with an increase of only 20%. Moreover, such phenomenon is not observed in women. We propose several hypotheses to explain the significant, but small, age- and sex-mediated variation in copy numbers. Among them are somatically acquired duplications that can affect some cells over time and result in an increase with age in men. In parallel, X chromosome monosomy, previously described in aging women, may explain the opposite phenomenon of TLR7/8 copy number decrease in those. Another explanation for men with X-linked gene copy increase can be due to the presence of female microchimerism, arising from foeto-maternal or twin sister exchange during in utero life. Such cells would carry 2 X chromosomes and contribute to the increased pool of X-linked genes among XY host cells. We have recently demonstrated that this can occur with the persistence of female cells from a female vanished twin in a 40 year male host. Nevertheless further studies are needed to explore whether i microchimerism increases with age and/or hormonal changes and whether increased copy number of TLR7/8 genes observed in elder men may have a real influence on TLR7/8 mRNA expression levels. ii) X chromosome epigenetic influence On the other hand, we have studied the patterns of X chromosome inactivation (XCI) among women with RA. XCI is an epigenetic dosage compensation mechanism used by mammals to ensure that XX females and XY males equalize X chromosome gene expression. Generally, there is a random inactivation of either the paternally-derived or the maternally-derived X chromosome in female tissues. A non-random XCI has been associated with many autoimmune diseases. In RA, we observe that, not only XCI is skewed among women with the disease, but it also correlates with the presence of predisposing HLA alleles, bearing the so- called “shared epitope”. The presence of the shared epitope often indicates severity of RA resulting in chronic inflammation and provoking a skewed XCI pattern by clonal selection over time. An interesting perspective would be to investigate XCI, with respect to the shared epitope, in a cohort of women before they have RA symptoms. Our findings highlight the importance of the X chromosome, on a genetic and epigenetic point of view, in the development of autoimmunity. The X chromosome, often neglected in studies on autoimmune diseases, is a fascinating chromosome for which we do not know all facets. A better understanding will not only allow explaining female predominance in autoimmune disorders, but also give clues on female advantages in immunity and life expectancy. ii RESUME (FRANÇAIS) Les femmes sont plus à risque que les hommes dans la plupart des maladies auto-immunes (MAI). Plusieurs hypothèses ont été soulevées pour expliquer ce biais sexuel. L'objectif de ma thèse est de comprendre la prédominance féminine dans les MAI rhumatismales, avec un accent particulier sur la polyarthrite rhumatoïde (PR) et sur le chromosome X.
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