GENES AND AUTOIMMUNITY - INTRACELLULAR SIGNALING AND MICROBIOME CONTRIBUTION Edited by Spaska Angelova Stanilova Genes and Autoimmunity - Intracellular Signaling and Microbiome Contribution http://dx.doi.org/10.5772/45733 Edited by Spaska Angelova Stanilova Contributors Hiroshi Tanaka, Ekua Weba Brenu, Lotti Tajouri, Kevin Ashton, Don Staines, Sonya Marshall-Gradisnik, Ramona Tallone, Giuseppe D'Annunzio, Andrea Accogli, Sara Bolloli, Renata Lorini, Natalie Cherepahina, Zaur Shogenov, Jamiliya Tabaksoeva, Murat Agirov, Sergey Suchkov, Mariya Bocharova, Mikhail Paltsev, Yuji Hiromatsu, Sergey Krynskiy, Artem Kostyakov, Dmitry Sergeevich Kostyushev, Dmitrii Gnatenko, Seunghee Cha, Adrienne Gauna, Iwona Ben-Skowronek, Irena Manolova, Spaska Stanilova, Stephen Pennington, Stella Ademowo, Oliver FitzGerald, Lisa Staunton Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2013 InTech All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. 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Publishing Process Manager Dejan Grgur Technical Editor InTech DTP team Cover InTech Design team First published March, 2013 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from orders@intechopen.com Genes and Autoimmunity - Intracellular Signaling and Microbiome Contribution, Edited by Spaska Angelova Stanilova p. cm. ISBN 978-953-51-1028-6 free online editions of InTech Books and Journals can be found at www.intechopen.com Contents Preface VII Section 1 Genes and Intracellular Signaling 1 Chapter 1 Genetic Susceptibility to Graves’ Ophthalmopathy 3 Junichi Tani and Yuji Hiromatsu Chapter 2 Gene Polymorphisms of Immunoregulatory Cytokines IL-10 and TGF-β1 in Systemic Lupus Erythematosus 33 Irena Manolova, Mariana Ivanova and Spaska Stanilova Chapter 3 Toll-Like Receptor 3 and Retinoic Acid-Inducible Gene-I Implicated to the Pathogenesis of Autoimmune Renal Diseases 59 Hiroshi Tanaka and Tadaatsu Imaizumi Chapter 4 Gene Expression Pattern Characterises Development of Multiple Sclerosis 75 Lotti Tajouri, Ekua W. Brenu, Kevin Ashton, Donald R. Staines and Sonya M. Marshall-Gradisnik Chapter 5 Costimulatory Molecules in Rheumatic Diseases Revisited with an Emphasis on Their Roles in Autoimmune Sjögren’s Syndrome 99 Adrienne E. Gauna and Seunghee Cha Chapter 6 Immune Synapses Between Lymphocytes and Target Cells in Autoimmune Thyroid Diseases 119 Iwona Ben-Skowronek and Roman Ciechanek Section 2 Infectious Agents and Host Inflammatory Response 131 Chapter 7 Microbiome and Autoimmunity 133 Natalie Cherepahina, Zaur Shogenov, Mariya Bocharova, Murat Agirov, Jamilyia Tabaksoeva, Mikhail Paltsev and Sergey Suchkov Chapter 8 Environmental Factors and Type 1 Diabetes Mellitus in Pediatric Age Group 151 Giuseppe d'Annunzio, Andrea Accogli, Ramona Tallone, Sara Bolloli and Renata Lorini Chapter 9 Common Mechanisms of Pathogenesis of Tissue-Specific Autoimmune Diseases: The Edited Model to Illustrate Those for IDDM and Multiple Sclerosis 183 S. A. Krynskiy, A. V. Kostyakov, D. S. Kostyushev, D. A. Gnatenko and S. V. Suchkov Chapter 10 Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Parallels with Autoimmune Disorders 205 Ekua W. Brenu, Lotti Tajouri, Kevin J. Ashton, Donald R. Staines and Sonya M. Marshall-Gradisnik Chapter 11 Biomarkers of Inflammatory Arthritis and Proteomics 237 Opeyemi S. Ademowo, Lisa Staunton, Oliver FitzGerald and Stephen R. Pennington ContentsVI Preface Recently, it has been a great challenge to acquire an in-depth knowledge in regards to the inner workings and interactions between the immune system and environmental factors along with their impact on human health. Environmental factors like growing pollution, changes in lifestyle habits, dietary compo‐ nents, as well as various microorganisms are interfering with components of our immune system driving a normal immune response to hyper- or hypo-reactivity. When the immune system becomes hyper-reactive it targets one’s own healthy cells leading to the destruction of tissues in the body, a process which is known as the onset of autoim‐ mune disease. The common target organs include the thyroid, adrenal, stomach, liver, pan‐ creas, kidneys, skin, joints, muscles and the nervous system. The organ specific autoantibodies often occur together with non-organ specific antibodies such as anti-DNA and anti-nucleoproteins in Systemic Lupus Erythematosus (SLE). Autoimmune disorders are known to affect a substantial number of people worldwide, demonstrating a gender bias and it is the second largest cause of chronic illness. They repre‐ sent the fifth leading cause of death among women in age groups up to 60. The main feature of the human immune system is the fine discrimination between self com‐ ponents from foreign antigens. Immunological tolerance is a state of unresponsiveness in‐ duced by prior exposure to a particular antigen, mostly self antigens. Thus, the body must establish self-tolerance mechanisms in order to avoid reactivity towards self components. One theory explains that breaking of self-tolerance is when some microorganisms (such as bacteria or viruses) or xenobiotics trigger the changes in immune regulation which results in autoimmune disorders. Recognition of the molecular pattern of a pathogen, which is distin‐ guishable from the host molecules is important for protective immune response and when mistaken, could often lead to autoimmunity. This process strongly depends on the individu‐ al genetics background in a person. Certain individuals are genetically susceptible to devel‐ oping autoimmune diseases. There are a number of genes that may plausibly be involved in the development of autoimmunity. It is known that genetics predisposition is associated with three main sets of genes, including immunoglobulins, T-cell receptors and major histo‐ compatibility complex (MHC), but are not restricted to them. The development of autoim‐ munity is also strongly influenced by inherited disease-associated single nucleotide polymorphisms rather than deletion or rearrangements. Cytokine, cytokine receptors and TLR-associated genes have recently attracted great interest as candidate genes for autoim‐ mune diseases. Over the past decade there has been great interest in testing candidate gene polymorphisms for evidence of their association with various autoimmune diseases. The ge‐ netic hallmarks of autoimmunity are undoubted, however particular genes and triggering intracellular signaling pathway remains elusive. Genes of cytokine and immune cell recep‐ tors regulating function of immune system are expressed under control of intracellular sig‐ naling pathway such as TLR signaling pathway, Fc receptors, receptors and ligands of immunological synapses, vitamin D receptors and other immune related genes. Two opposite hypothesis are currently under investigation. One of them (hygiene hypothe‐ sis) discusses whether the reduced exposure to certain infections, as a result of improved hygiene and living conditions, may be responsible for the increased incidence in autoim‐ mune conditions. The other hypothesis is that autoimmune diseases might be a conse‐ quence of post-infections conditions. Despite this contradiction, infection agents and their antigens obviously play a pivotal role in the development of autoimmunity through inter‐ action with the immune system. Arguments that support the role of infection in specific autoimmune diseases come from clinical, epidemiological and laboratory studies. New da‐ ta demonstrates that the gut flora compositions can also influence the development of au‐ toimmune diseases. For example, the use of probiotics containing lactobacilli decreases the incidence of diabetes in NOD mice. At the same time, a range of differing factors such as dietary supplements, hormones, alcohol consumption, vitamins and drugs, cigarette smok‐ ing, etc. implicated in autoimmune disease onset. Dietary antigens also stimulate antigen receptors and aberrant immune response can progress to autoimmunity. According to the afore discussed, it seems obvious that neither genetic predisposition nor environmental factors alone are sufficient to cause the disease. The triggering factors and intracellular signaling pathway crosstalk are currently under extensive investigation with high hopes for revealing the autoimmunity clue. In conclusion, autoimmune diseases develop in genetically predisposed organisms as a re‐ sult of a specific triggering agent (infectious or noninfectious), causing dysfunction in the immune system activity with subsequently developed abnormal autoimmune mechanism affecting its own cells and tissues of the organism. This book attempts to seize the new opportunities for moving research forward, leading to a new approach for the prevention and treatment of autoimmune diseases. The first section of this book is focused on genes, gene expression and signaling pathways involved in autoim‐ mune pathogenesis. The second one attempts to present current data for interaction of mi‐ crobiota with human immune system, which are implicated in the development of autoimmune disease. We hope the book will be useful for anyone wanting to expand their knowledge of the oc‐ currence and mechanisms of autoimmunity. Dr Spaska Angelova Stanilova, PhD, Dsc Professor of Molecular Biology and Immunology Head of Department of Molecular Biology, Immunology and Medical Genetics Faculty of Medicine, Trakia University Bulgaria PrefaceVIII Section 1 Genes and Intracellular Signaling [...]... I GO HLA-C*07 HLA-B*08 synapse genes HLA class II HT HLA-DR3 HLA-A2 HLA-DPB 2.1/8 HLA-DR3 HLA-DR4 HLA-DR5 HLA-DR7 HLA-DR7 HLA-DRB1 HLA-DQB1*03 HLA-DRB3 HLA-DQw7 HLA-DRB1*04 HLA-DQB1*0301 HLA-DRB4*0101 HLA-DRw53 HLA-DRw9 CTLA-4 CTLA-4 PTPN22 CTLA-4 PTPN22 PTPN12 CD40 T cell regulation FOXP3 FOXP3 CD25 Thyroid specific Thyroglobulin genes DIO 2 TSHR Thyroglobulin 13 14 Genes and Autoimmunity - Intracellular. .. IL-1α and- β are pro-inflammatory cytokines, and the IL-1receptor antagonist (RA) competes for receptor binding with IL-1α and- β [81] Retro-orbital fibroblasts derived from GO patients expressed and secreted significantly reduced levels of intracellular and soluble IL-1RA [82] Thus, an imbalance between IL-1 and IL-1RA may play an important role in the pathogenesis of GO and gene polymorphisms in IL-1α,... Thyroglobulin genes DIO 2 TSHR Thyroglobulin 13 14 Genes and Autoimmunity - Intracellular Signaling and Microbiome Contribution Categories GD including GO GO HT Cytokines or TNF-α TNF-α Cytokine receptors IL-1α IL-4 IL-1β TGF-β IL-1RA IFN-© IFN-γ IL-23R Other immunological NF-κB NF-κB molecules CD226 ICAM-1 FCRL3 TLR-9 SCGB3A2 CD86 IFIH1 CD103 VDR GR Others VDR ESR2 Each genetic locus is referenced in... (2004) , 14, 51 0-5 20 27 28 Genes and Autoimmunity - Intracellular Signaling and Microbiome Contribution [61] Zaletel, K, & Gaberscek, S Hashimoto’s Thyroiditis: From Genes to the Disease Curr Genom (2011) , 12, 57 6-5 88 [62] Tani, J, Yoshida, K, Fukazawa, H, Kiso, Y, Sayama, N, Mori, K, Aizawa, Y, Hori, H, Nakasato, N, & Abe, K Hyperthyroid Graves’ disease and primary hypothyroidism caused by TSH receptor... peripheral tolerance to self-antigens In murine studies, upregulation of Treg cells suppressed experimental autoimmune thyroiditis [37], while depletion 7 8 Genes and Autoimmunity - Intracellular Signaling and Microbiome Contribution of Tregs increased their susceptibility to experimental GD [38] Treg cells are characterized by constitutively expressing CD25, CTLA-4, and glucocorticoid-induced tumor necrosis... for HLA-DRB1, which has a critical role in antigen presentation, in the devel‐ 15 16 Genes and Autoimmunity - Intracellular Signaling and Microbiome Contribution opment of GO [80] However, contradictory reports also exist [80, 90] HLA-DR7 alleles are also reported to have an association with the development of GO [91], and several isolated studies have shown a weak association between HLA-DR4, HLA-DPB... VIb 19 20 Genes and Autoimmunity - Intracellular Signaling and Microbiome Contribution Figure 2 A 42-year-old female with bilateral proptosis A) She has right lid retraction in primary gaze (Darylmple’s sign) and lid edema B) However her eye movement was normal C) MRI imaging shows all her extraocular muscles are intact This case is NOSPECS class is Ia, IIa, IIIb IV0, V0, VI0 Figure 3 A 51-year-old female... HLA-C in Graves’ disease that eclipses the classical HLA-DRB1 effect Hum Mol Genet (2007) , 16, 214 9-2 153 [19] Ploski, R, Szymanski, K, & Bednarczuk, T The Genetic Basis of Graves’ Disease Curr Genom (2011) , 12, 54 2-5 63 [20] Tomer, Y Genetic susceptibility to autoimmune thyroid disease: past, present, and future Thyroid (2010) , 20, 71 5-7 25 23 24 Genes and Autoimmunity - Intracellular Signaling and Microbiome. .. Biosci (2011) , 16, 78 3-8 02 [41] Tomer, Y, Ban, Y, Concepcion, E, Barbesino, G, Villanueva, R, Greenberg, D A, & Davies, T F Common and unique susceptibility loci in Graves and Hashimoto dis‐ 25 26 Genes and Autoimmunity - Intracellular Signaling and Microbiome Contribution eases: results of whole-genome screening in a data set of 102 multiplex families Am J Hum Genet (2003) , 73, 73 6-7 47 [42] Hodge, S... cells, including interferon (IFN )- , have been well studied among HT patients The T allele of the +874A/T IFN-γ SNP, which causes an increased production of IFN-γ, was reported to be associated with the severity of hypothyroidism in HT patients [70] However, a higher 11 12 Genes and Autoimmunity - Intracellular Signaling and Microbiome Contribution frequency of severe hypothyroidism was also observed . 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