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Variation of Complement Factor H and Mannan Binding Lectin in Human

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Variation of Complement Factor H and Mannan Binding Lectin in Human Variation of Complement Factor H and Mannan Binding Lectin in Human Systemic and Vascular Immune-Mediated Diseases Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Kathryn Jean Kitzmiller Graduate Program in Integrated Biomedical Science Program The Ohio State University 2009 Dissertation Committee: Professor Carlos Alvarez Professor Daniel Birmingham Professor Heithem El-Hodiri Professor Haikady Nagaraja Professor C. Yung Yu, Advisor Copyright by Kathryn Jean Kitzmiller 2009 Abstract Recognizing multiple pathogenic challenges, the vertebrate immune system devises numerous layers of inherent and somatic changes. Heritable inherent immune diversity among different individuals is characterized by gene copy number variation (CNV) and polymorphisms of coding and non-coding DNA sequences that collectively contribute to quantitative and qualitative diversities of immune proteins. We hypothesize that inherent genetic diversity of the immune system confers a spectrum of intrinsic strengths among individuals of a population to defend against infections, but inflicts different susceptibilities for immune-mediated diseases. As effectors of immune defense, the complement protein cascades engage in self and nonself differentiation and hemostasis. Inherited or acquired complement deficiency predisposes an individual to recurrent infections and compromises immune tolerance leading to diseases such as Systemic Lupus Erythematosus (SLE), Antiphospholipid Syndrome (APS), and Age-Related Macular Degeneration (AMD). Multiple organ involvement and autoantibody production are characteristics of SLE as well as antiphospholipid antibodies (aPL) and thrombosis which also occurs in APS. Vascular and cellular abnormalities of AMD cause elderly vision loss. Factors affecting racial disparity and severity in SLE and AMD are not well understood at present. ii Complement Factor H (CFH) regulates complement activation in plasma and on host cell surfaces to protect against complement-mediated damage. Mannan Binding Lectin (MBL) deficiency associates with increased infection, thrombosis, and autoimmunity. To determine how complement variation contributes to intrinsic immune strength and diversity, we elucidated MBL and CFH variants in healthy subjects of multiple races, and subjects with SLE, APS, and AMD. PmeI Pulsed-Field Gel Electrophoresis and TaqI and PshAI-PvuII Restriction Fragment Length Polymorphism-Southern blots revealed the complexity of the CFH gene region. We established a 76-kb CNV of CFHR3 and CFHR1 (CFHR3-R1) present at 0, 1, or 2 copies, and varies among healthy subjects of different races (χ2=181, p=2.28x10-36). Increased CFHR3-R1 deficiency demonstrates a dosage effect for African American SLE risk such that CFHR3-R1 heterozygous deficiency associates with an OR of 1.67 (95% C.I. 1.09-2.61, p=0.03) whereas CFHR3-R1 homozygous deficiency has an OR of 1.94 (95% C.I. 1.12-3.38, p=0.02). Higher copy numbers of CFHR3-R1, as determined by real-time PCR in European subjects, associates with neovascular AMD (χ2=6.8; p=0.03). CFHR3-R1 has a dual role in racial disparity: high copy numbers in European American AMD risk and low copy numbers in African American SLE risk. Phenotypic variation of plasma proteins for CFH detected by radial immunodiffusion, and functional MBL detected by ELISA, enable the iii investigation of their role in SLE and APS. Subjects with aPL-associated SLE with thrombosis have reduced protein levels of CFH and MBL compared to aPL- only subjects (CFH: 48.9±9.7 vs 54.5±15.4 mg/dL, p=0.001; MBL: 0.114 ± 0.128 vs 0.173 ± 0.192 mg/dL, p=0.0041). Multiple promoter polymorphisms and exon1 variants in MBL correlate with quantitative variations of functional MBL levels among SLE cases. In conclusion, quantitative and qualitative variation of CFH and MBL contribute to immune-mediated, human systemic and vascular diseases. Low CFHR3-R1 copy number is a significant risk factor for African American SLE. Identification of subjects at risk or with severe disease manifestations can lead to more accurate diagnoses and reduced disease severity through precautionary intervention. iv This document is dedicated to my family. Your continuous support and encouragement have enabled me to achieve this and many other successes. Thank you especially for amusing me with your ever-changing interpretations of my dissertation topic and for constantly asking if I have “cured lupus” yet. v Acknowledgments I am most grateful for the continuous support and mentorship from my advisor, Dr. C. Yung Yu. Through his actions and constant encouragement he has taught me patience, tolerance, and inspiration. He has always humored my optimism and thinking outside the box. I would like to thank him sincerely for the opportunity to train in his laboratory, and prepare me for all my future endeavors. He has been an inspirational advisor and leader who has enduring encouragement and support. The magnitude of this work would not be possible without contributions by past and present colleagues, especially Dr. Erwin Chung, Dr. Yan Yang, Dr. Stephanie Savelli, and Dr. Kapil Saxena for their assistance and fundamental work. I extend a special token of gratitude to Dr. Yee Ling Wu and Ms. Bi Zhou for their technical expertise and guidance in the laboratory, as well as Ms. Nazreen Esack for assistance and friendships. I wish all of you many successes. I am grateful for all the volunteers and donors that made this body of work possible. I would like to thank all the SLE patients and their families for participating in research studies. This work was generously sponsored from funding agencies including National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Disease, National vi Institute of Diabetes and Digestive Kidney Diseases, and the Lupus Foundation of America. I thank all the colleagues in the Ohio SLE study group, especially Dr. Lee Hebert, Dr. Brad Rovin, Dr. Dan Birmingham, and Dr. Haikady Nagaraja for their efforts in establishing and maintaining such a valuable resource. I thank Dr. Gloria Higgins, Dr. Robert Rennenbohn, and Ms. Karla Jones at Nationwide Children’s Hospital for assisting with the recruitment of pediatric SLE patients and healthy controls. I would like to thank all our collaborators who have provided us the priceless gift of samples including Dr. Joann Moulds at Drexel University, Philadelphia, Pennsylvania, Dr Mark Pepys at University College London, London, Britain, Dr. Rando Allikmets at Columbia University, New York, New York, Dr. Joe Ahearn at University of Pittsburgh, Pittsburgh, Pennsylvania, Dr. Robert A.S. Roubey at the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, and Dr. Betty Tsao at University of California, Los Angeles, Los Angeles, California. I would like to acknowledge the support of The Research Institute at Nationwide Children’s Hospital and the Ohio State University Integrated Biomedical Science Graduate Program. Thank you to my graduate dissertation committee members Dr. Carlos Alvarez, Dr. Dan Birmingham, Dr. Heithem El- Hodiri, Dr. Haikady Nagaraja for your assistance, attendance at meetings, and support. Thank you Dr. Jaclyn McAlees and Dr. Joseph Carl and all my classmates and friends in the IBGP program I have made along the way. Thank vii you to Mrs. Lisa Huber, Dr. David Cunningham, Dr. Holly Moose, Dr. Reyna Martinez-Deluna, Mr. Sadeq Kharzai, Mr. Girish Rajgolikar for listening and sharing wisdom throughout this process. Last, but not least I would like to thank my family for their support and encouragement. Thanks and love to Aunt Joan Mickunas for giving of yourself countless times. Finally, thanks to my mom and dad - I could not have asked for anything more. viii Vita 1998…………………………………………………………..Akron North High School 2001…………………………………..B.S. Chemistry, Youngstown State University 2004…………………………………..M.S. Chemistry, Youngstown State University 2004 to present ...................................... …………..Graduate Research Associate Integrated Biomedical Sciences The Ohio State University Publications Kitzmiller, K.J, Yang, Y., Wu, Y.L., Zhou, B., Chung, E., Yu, C.Y. (2009). Determining the copy number variation (CNV) of human Complement Factor H Related Genes: from Southern blots to real-time PCRs. J Immunol, 182, 136.30, Abstract. Saxena, K., Kitzmiller, K.J., Wu, Y.L., Zhou, B., Esack, N., Hiremath, L., Chung, E., Yang, Y., Yu, C.Y. (2009) Great genotypic and phenotypic diversities associated with copy-number variations of complement C4 and RP-C4-CYP21- TNX (RCCX) modules: A comparison of Asian-Indian and European American populations. Mol Immunol, 49, 1289-1303. Wu, Y.L., Yang, Y., Chung, E., Zhou, B., Kitzmiller, K.J., Savelli, S., Nagaraja, H., Birmingham, D., Tsao, B., Rovin, B., Hebert, L., and Yu, C.Y. (2008) Phenotypes, genotypes and disease susceptibility associated with gene copy number variations: complement C4 CNVs in European American healthy subjects and those with systemic lupus erythematosus. Cytogenet Genome Res, 123, 131-141.*Featured on cover ix Yang, Y., Chung, E., Wu, Y.L., Savelli, S., Nagaraja, H., Zhou, B., Hebert, M., Jones, K., Shu, Y., Kitzmiller, K.J., Blanchong, C., McBride, K., Higgins, G., Rennebohm, R., Rice, R., Hackshaw, K., Roubey, R., Grossman, J., Tsao, B., Birmingham, D., Rovin, B., Hebert, L., Yu, C.Y. (2007). Gene copy-number variation and associated polymorphisms of complement component
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