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Heat Shock Proteins in Systemic Lupus Erythematosus

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Heat Shock Proteins in Systemic Lupus Erythematosus CYTOKINES AND THE REGULATION OF HEAT SHOCK PROTEINS IN SYSTEMIC LUPUS ERYTHEMATOSUS by Barry James Marc Ripley B.Sc., PGDlp (LSHTM), M.Sc. Thesis submitted for the degree of Ph D. Institute of Child Health, University College London 2001 ProQuest Number: U643772 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest U643772 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 To my family for all their love and support Abstract Previous studies have reported elevated levels of the 90 kDa heat shock protein (Hsp 90) and autoantibodies to Hsp 90 in a subset of patients with systemic lupus erythematosus (SLE). However, the mechanisms leading to the overexpression of Hsp 90 in SLE and a link between this event and the induction of Hsp 90 autoantibodies, have remained unclear. Recent studies have shown that the cytokine IL-6, which is elevated in SLE, activates Hsp 90 gene expression in cultured cells via specific transcription factors, that include STAT-3. In view of the known role of STAT proteins in signalling pathways of the cytokine IL-10, the effect of IL-10 on Hsp 90 levels in different cells was investigated. IL-10 enhanced the expression of Hsp 90 in cultured cells. In reporter gene assays, IL=10 activated both the Hsp 90a and Hsp 90p promoters directly. Activation of the Hsp 90p promoter was mediated by a short specific region of the promoter which contains a binding site for STAT-3. Cytokines and Hsps, were quantified in individual blood samples from patients with SLE. Levels of Hsp 90 positively correlated with levels of IL-6 but not IL-10, in patients with SLE. Furthermore, this correlation was enhanced in patients who overexpressed Hsp 90 (a subset of patients associated with HLA DR3 negativity). A link between Hsp 90 overexpression and the development of Hsp 90 autoantibodies was also investigated. Antibodies to Hsps in patients with SLE were quantified. Overexpression of Hsp 90 in SLE correlated with raised levels of antibodies to Hsp 90 in the same patients. Furthermore, antibodies to Hsp 90 were associated with active general disease features of SLE. These results support a role for IL-6 in the overexpression of Hsp 90, leading to raised levels of antibodies to Hsp 90 and active disease in SLE. Table of Contents Page Number List of Figures ...............................................................................................12 List of Tables ................................................................................................ 18 Abbreviations ................................................................................................23 List of Publications ....................................................................................... 25 Acknowledgements .......................................................................................26 Chapter 1. Introduction Section 1.1: The Heat Shock Proteins Introduction .................................................................................................. 28 Heat Shock Protein Families and Biological Functions ...............................29 The Hsp 90 Family...........................................................................31 The Hsp 70 Family...........................................................................38 The Hsp 60 Family...........................................................................40 Small Hsps and Ubiquitin ................................................................ 41 Conditions that Induce the Expression of Heat Shock Proteins ................... 43 Transcriptional Regulation of Heat Shock Protein Expression ....................45 Cytokines ......................................................................................... 47 Interleukin-10...................................................................................48 Interleukin-6.....................................................................................48 IL-10 and IL-6 Activate the STAT Family of Transcription Factors.................................................................. 50 Page Number IL‘6 but not IL=10, Activates Transcription Factors of the C/EBP Family............................................................ 53 Role of Interleukin-6 in Hsp 90 Gene Regulation............................. 53 Summary....................................................................................................... 54 Section 1.2: The Role Of Heat Shock Proteins in the Immune System and Pathogenesis of Autoimmune Disease Introduction ...................................................................................................56 Self/Non-Self Discrimination Within the Immune System...........................57 Lymphocytes..................................................................................... 57 B Cells............................................................................................... 58 T Cells................................................................................................59 Thymic Selection of T Cells and Self-Tolerance .............................. 60 Heat Shock Proteins and the Immune System ...............................................61 Antigen Processing and Presentation ................................................ 61 Heat Shock Proteins and Infection .................................................... 62 Cell Surface Expression of Heat Shock Proteins...............................63 Heat Shock Proteins and Autoimmune Disease ............................................64 Antibodies to Heat Shock Proteins ................................................... 64 T Cell Responses to Heat Shock Proteins ......................................... 68 Summary.......................................................................................................69 Section 1.3: Systemic Lupus Erythematosus Introduction ...................................................................................................70 Definition and Classification ........................................................................ 70 Epidemiology ................................................................................................73 Prevalence .........................................................................................73 Page Number Clinical Features of SLE ............................................................................... 74 Non-Specific Features ....................................................................... 75 Dermatological Involvement .............................................................75 Musculoskeletal Involvement ............................................................75 Renal Disease....................................................................................76 Involvement of the Nervous System ................................................. 77 Haemopoietic Involvement ............................................................... 77 Cardio-Respiratory/-V ascular Involvement ...................................... 78 Management ..................................................................................................79 Prognosis and Survival ..................................................................................79 Immunopathology in SLE ............................................................................. 80 Genetic Susceptibility ....................................................................... 80 Sex Hormones....................................................................................81 Major Histocompatibility Complex...................................................82 Complement Dejîciencies..................................................................83 Immune Dysregulation and Cellular Abnormalities in SLE ............. 85 B Lymphocytes.................................................................................. 86 Cytokines........................................................................................... 86 Apoptosis...........................................................................................89 Autoantibodies...................................................................................90 Experimental Models of SLE.............................................................91 Summary ....................................................................................................... 93 Section 1.4: The Role of Hsps In SLE Introduction ................................................................................................... 94 The Expression of Heat Shock Proteins in SLE ............................................94 Surface Expression of Hsp 90 in SLE ...........................................................97 Page Number Antibodies to Hsps in SLE ............................................................................97 Hsp 90 Expression in MRUlpr/lpr Mice......................................................98 Section 1.5: Aims of Dissertation ..........................................101
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