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The Roles of Complement C4A and C4B Genetic Diversity and HLA DRB1 Variants on Disease Associations with Juvenile Dermatomyositis and Systemic Lupus Erythematosus

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The Roles of Complement C4A and C4B Genetic Diversity and HLA DRB1 Variants on Disease Associations with Juvenile Dermatomyositis and Systemic Lupus Erythematosus DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Katherine E. Lintner, B.S. Graduate Program in Molecular, Cellular and Developmental Biology The Ohio State University 2016 Dissertation Committee: Carlos Alvarez, Ph.D. Heithem El-Hodiri, Ph.D. Wael Jarjour, M.D. Yusen Liu, Ph.D. Chack-Yung Yu, D.Phil., Advisor Copyright by Katherine E. Lintner 2016 Abstract Complement C4 is an immune protein with a wide range of effector functions, including disposal of apoptotic materials, clearance of immune complexes, and activation of the classical complement pathway resulting in cytolysis of microbes. Homozygous deficiencies of C4 or early complement components (C1q, C1r, or C1s), albeit rare, are strongly associated with the autoimmune disease systemic lupus erythematosus (SLE). Much more common than a complete genetic deficiency is “low” gene copy number (GCN) of C4, which varies among human genomes from two to eight copies. Low GCN of C4, specifically of the isotype C4A, is associated with SLE disease risk. However, it is known that C4A-deficient haplotypes in European Americans are in strong linkage disequilibrium (LD) with HLA allele DRB1*0301 on chromosome 6, which has been associated with other autoimmune diseases, including juvenile dermatomyositis (JDM). It remains a puzzle whether C4A deficiency, DRB1*0301, or both are responsible for the primary disease association because of the strong LD exhibited between the two genetic variants. We assessed GCNs for C4A, C4B, and HLA-DRB1 alleles in genetic risk of JDM. C4A deficiency was a risk factor for JDM independent of DRB1*0301, but the effect size was stronger when C4A deficiency and DRB1*0301 were present together. JDM patients with C4A deficiency had higher prevalence of elevated serum muscle ii enzymes at disease diagnosis and elevated erythrocyte-bound C4-derived activation products (E-C4d). We also observed that C4A deficiency is a strong risk factor for pediatric SLE susceptibility as is the case for adult SLE reported previously, but the effect size was greater in pediatric populations. Our regression analyses of Caucasian SLE patients and controls suggested that DRB1*0301 was likely secondary to C4A deficiency on disease susceptibility. Given the common observation of C4A deficiency in patients afflicted with JDM or SLE, a logical step forward would be the establishment of C4-based therapy for these patients. In a series of luciferase reporter assays, we confirmed the 3’ long terminal repeat (3’LTR) that flanks a retroviral insertion in intron 9 of C4 displays promoter activity, which could possibly initiate an antisense C4 transcript from exon 9 to exon 1. Moreover, we demonstrated the 3’LTR, in both orientations, enhanced C4 promoter activity in different human cultured cells. In healthy subjects from three different races, we showed a significant, negative correlation between the retroviral insert and C4 plasma protein levels. Cell culture assays and genotype-phenotype data indicate that the retroviral 3’LTR may interfere with C4 gene expression, possibly through antisense inhibition. Several observations here require thoughtful and investigative extensions of this work. It is of interest to study the 3’LTR and other cis-acting elements that may affect C4 gene expression. Furthermore, increasing the sample size of the study population and analyzing complement and HLA genetic risk factors in autoimmune diseases in other races will allow for a greater understanding of disease pathways, identify any common or iii race-specific genetic factors, and impact the field of human health by strengthening the prevention, treatment, maintenance, or cure of JDM, SLE, or other human immune- mediated diseases. iv Dedicated to Anthony Miller. His love and encouragement wholeheartedly helped me to complete this document. v Acknowledgments I wish to thank my advisor Dr. C. Yung Yu for supporting me during my time in his laboratory. He has given me every opportunity to succeed as a researcher, pushing me to limits that I sometimes did not know I could (or want to!) reach. He has taught me not only about complement genetics and immunology, but also about history, politics, and of course sports, including my favorites the Cincinnati Bengals, Cincinnati Reds, and The Ohio State Buckeyes. Thank you, Dr. Yu, for sharing all of your knowledge and passion with me. I also wish to thank my graduate studies committee- Carlos Alvarez, Heithem El- Hodiri, Wael Jarjour, and Yusen Liu. Their thoughtful input, challenging questions, and dedicated time to my committee meetings and presentations have helped me to enhance my research and complete this degree. In addition to my committee members, I thank Dr. John P. Atkinson (Washington University School of Medicine) for his insights and assistance with writing of my Chapter 1- Introduction. As for the rest of the 4th floor Wexner crew, I wish to thank the following people: Bi Zhou, for relentlessly performing DNA and cell isolation from patient blood samples and Southern blots to obtain the precious RCCX genotypes for all of our recruited human subjects; Carolyn Moore, for her administrative support; Jessi Buescher and Jennifer vi Bosse, for their friendship and willingness to lend a listening ear, when all I wanted to do was complain; and Dr. Loyal Coshway, for her friendship and moral support. The bulk of my research and greatest accomplishment of my Ph.D. was the publication of our JDM study. Undoubtedly, this project took a number of years as well as a number of collaborators. I wish to thank Dr. Rabheh Abdul-Aziz and Dr. Charles Spencer for their role in recruiting JDM patients. I also thank Dr. Abdul-Aziz for her assistance in helping me to obtain important clinical data. This manuscript would not exist without the collaboration of researchers in the Environmental Autoimmunity Group at the National Institute of Environmental Health Sciences. I wish to thank Dr. Lisa Rider, Dr. Terrance O’Hanlon, and Dr. Frederick Miller for their efforts in recruiting JDM patients and shipping blood and DNA samples for use in our study and for their essential input regarding data analysis and manuscript production. I must say that I would not be where I am in life without the support of my family. My parents have always instilled in me the importance of education. In the words of my father, my career has been a “professional student.” I told you I would be finished someday, Pops! No more student. Onward to a career… Although my older sister Emily and twin brother Rodney live multiple states away, I always looked forward to visiting with them and their families. It was the best way to break away from school for a bit. My nieces are the light of my life. Last but definitely not least, I want to express my sincere gratitude and love for my fiancé, Anthony Miller. We met in seminar class during our first year of graduate school. Although stressful and overwhelming at times, graduate classes were much more vii enjoyable with him by my side. He has stood by my side, never judgmental or critical, during my candidacy exam, important academic presentations, stages of manuscript writing and, of course, during the process of writing this document. So many times I wanted to give up. So many times I would complain every day about the same thing. He showed me nothing but love, encouragement, and empathy. Someday (very soon, I hope!) I can show him the same support as he begins to prepare his dissertation. Thank you, Anthony, for loving me through this. viii Vita 2001-2005………………………………..Stephen T. Badin High School, Hamilton, OH 2005-2009………………………………..B.S. Biology, Walsh University, North Canton, OH 2011-2016………………………………..Graduate Research Associate, Molecular, Cellular, & Developmental Biology, The Ohio State University, Columbus, OH Publications Lintner K, Wu YL, Yang Y, Spencer C, Hauptmann G, Hebert L, Atkinson J, Yu CY . (2016) Early components of the complement classical activation pathway in human systemic autoimmune diseases. Frontiers in Immunology 7:36. Chen JY, Wu YL, Mok MY, Wu YJ, Lintner K, Wang CM, Chung EK, Yang Y, Zhou B, Wang H, Yu D, Alhomosh A, Jones K, Spencer CH, Nagaraja HN, Lau YL, Lau CS, Yu CY. (2016) Effects of complement C4 gene copy number variations, size dichotomy and C4A deficiency on genetic risk and clinical presentation of East-Asian SLE. Arthritis and Rheumatology doi: 10.1002/art.39589 ix Lintner K, Patwardhan A, Rider L, Abdul-Aziz R, Wu YL, Lundstrom E, Padyukov L, Zhou B, Alhomosh A, Newsom D, White P, Jones K, O’Hanlon T, Miller F, Spencer C, Yu CY. (2015) Gene copy number variations of complement C4 and C4A deficiency as genetic risk factors and in pathogenesis of juvenile dermatomyositis. Annals of the Rheumatic Diseases doi :10.1136/annrheumdis. 2015.207762 Yu CY, Driest K, Wu YL, Lintner K, Patwardhan A, Spencer C, Rigby W, Hebert L, Hauptmann G. (2013) Complement in rheumatic diseases. Encyclopedia of Medical Immunology: Autoimmune Diseases. New York: Springer Science. P. 286-302 Yan J, Meng X, Wancket L, Lintner K, Nelin L, Chen B, Francis K, Smith C, Rogers L, Liu Y. (2012) Glutathione reductase facilitates host defense by sustaining phagocytic oxidative burst and promoting the development of neutrophil extracellular traps. Journal of Immunology 188(5):2316-27 Field
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