Ebook Epigenetics and dermatology: Part 2
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Ebook Epigenetics and dermatology: Part 2
CHAPTER12Epigenetics and Systemic SclerosisNezdm Altorok1 and Amr H. Sawalha2,3 ’Division of Rheumatology, Department of Internal Medicine, University Ebook Epigenetics and dermatology: Part 2y of Toledo Medical Center, Toledo, OH 2Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI ^Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI12.1INTRODUCTIONScleroderma is a term that encompasses most forms of th Ebook Epigenetics and dermatology: Part 2ickened and sclerotic skin, including both localized (morphea, linear scleroderma, etc.) and systemic sclerosis (SSc) (limited, diffuse) variants. SScEbook Epigenetics and dermatology: Part 2
is a complex multisystem autoimmune disease that is characterized by three pathological hallmarks: activation of the immune system, vascular injury, CHAPTER12Epigenetics and Systemic SclerosisNezdm Altorok1 and Amr H. Sawalha2,3 ’Division of Rheumatology, Department of Internal Medicine, University Ebook Epigenetics and dermatology: Part 2 distinguished by the extent of skin thickening; IcSSc is characterized by skin thickening that is confined to the extremities distal to the elbows and knees with or without facial involvement, whereas dcSSc is characterized by skin thickening that involves areas proximal to the elbows and knees, in Ebook Epigenetics and dermatology: Part 2cluding the trunk I2|. Besides the extent of skin involvement, the two subsets of SSc have different patterns of organ involvement, autoantibody profiEbook Epigenetics and dermatology: Part 2
les, and survival rates. For instance, patients with IcSSc arc at risk for developing subcutaneous calcinosis, telangiectasia, malabsorption, digital CHAPTER12Epigenetics and Systemic SclerosisNezdm Altorok1 and Amr H. Sawalha2,3 ’Division of Rheumatology, Department of Internal Medicine, University Ebook Epigenetics and dermatology: Part 2l disease, and25012. EPIGENETICS AND SYSTEMIC SCLEROSISTABLE 12.1 Examples of Environmental Agents Linked to SScOccupational exposuresWelding; silica dusts; toxic oil; xenobiotics; pesticides; ultraviolet light exposure; organic solvents; epoxy resins; benzene; trichloroethylene; xylene; urea formal Ebook Epigenetics and dermatology: Part 2dehyde; and vinyl chlorideInfectious agents1 luman cytomegalovirusDietL-TryptophanDrugsMethysergide; pentazocine; cocaine; talc; heroin; bleomycin; etEbook Epigenetics and dermatology: Part 2
hosuximide; vitamin K; and amphetaminesmyocardial involvement. Anti-topoisomerase 1 (Scl-70) and anti-RNA polymerase antibodies are common in dcSSc, aCHAPTER12Epigenetics and Systemic SclerosisNezdm Altorok1 and Amr H. Sawalha2,3 ’Division of Rheumatology, Department of Internal Medicine, University Ebook Epigenetics and dermatology: Part 2 major challenge. Current hypotheses suggest a possible infectious or perhaps chemical agent that activates the immune system that, in turn, causes vascular injury/dysfunction and persistent activation of fibroblasts [31. The end product of this interaction is deposition of collagens and extracellul Ebook Epigenetics and dermatology: Part 2ar matrix (ECM) glycoproteins in organs, which cause organ damage and dysfunction.Over the last few years it became evident that substantial epigenetiEbook Epigenetics and dermatology: Part 2
c aberrancies are present in SSc. These findings stem from candidate gene and epigenome-wide studies and are supported by the striking geographic clusCHAPTER12Epigenetics and Systemic SclerosisNezdm Altorok1 and Amr H. Sawalha2,3 ’Division of Rheumatology, Department of Internal Medicine, University Ebook Epigenetics and dermatology: Part 2 The environmental factors that are involved in the pathogenesis of SSc are by large uncharacterized. However, epidemiological and experimental data have linked a number of occupational exposures to the development of SSc (Table 12.1).In this chapter, we briefly discuss the pathogenesis of SSc; we t Ebook Epigenetics and dermatology: Part 2hen explore evidence for epigenetic aberrancies in DNA methylation, histone code, and altered expression of microRNAs (miRNAs) across different cell tEbook Epigenetics and dermatology: Part 2
ypes that are involved in the pathogenesis of SSc.12.2PATHOGENESIS OF SScThe current paradigm suggests that the pathogenesis of SSc is based upon a coCHAPTER12Epigenetics and Systemic SclerosisNezdm Altorok1 and Amr H. Sawalha2,3 ’Division of Rheumatology, Department of Internal Medicine, University Ebook Epigenetics and dermatology: Part 2issue fibrosis [51.12.2 PATHOGENESIS OF SSc2511Activation of the immune systemSSc is a connective tissue disorder that is characterized by chronic deregulation of the immune system. It appears that the most prominent effect of immune system deregulation occurs in the early phases of SSc, based on th Ebook Epigenetics and dermatology: Part 2e observation that there are significant inflammatory cell infiltrates in the skin in the early phases of SSc [61. In addition, there is significant uEbook Epigenetics and dermatology: Part 2
pregulation of growth factors and cytokines in skin and sera samples, respectively, from patients with SSc 171. Moreover, SSc is characterized by the CHAPTER12Epigenetics and Systemic SclerosisNezdm Altorok1 and Amr H. Sawalha2,3 ’Division of Rheumatology, Department of Internal Medicine, University Ebook Epigenetics and dermatology: Part 2ymphocytes in SScT lymphocytes contribute to the pathogenesis of SSc.Although the total number of peripheral blood T lymphocytes in SSc is not increased and in fact may be lower than that in healthy people, there is evidence for activation of circulating T lymphocytes in SSc [81. in addition, there Ebook Epigenetics and dermatology: Part 2is evidence for T-lymphocyte infiltration in lung and skin tissues in the early phases of SSc [9].b.B lymphocytesB cells, among other immune cells, arEbook Epigenetics and dermatology: Part 2
e activated in SSc, as manifested by the presence of circulating antibodies, hypergammaglobulinemia, stimulation of polyclonal B cells, and overexpresCHAPTER12Epigenetics and Systemic SclerosisNezdm Altorok1 and Amr H. Sawalha2,3 ’Division of Rheumatology, Department of Internal Medicine, University Ebook Epigenetics and dermatology: Part 2 is reduced, but they are activated [111. Human B lymphocytes are a source of transforming growth factor-3 (TGF-3) and express receptors for TGF-3 1121, and B lymphocytes secrete IL-6. TGF-3 and IL-6 may activate fibroblasts and induce upregulation of collagen production.c.Other immune cellsIn SSc, Ebook Epigenetics and dermatology: Part 2several cell types contribute to activation of the immune system; for example, dendritic cells, macrophages, and natural killer cells play an importanEbook Epigenetics and dermatology: Part 2
t role in the production of type 1 interferon, which is upregulated in SSc [13].2Vascular injury/dysfunctionVascular damage occurs early in the courseCHAPTER12Epigenetics and Systemic SclerosisNezdm Altorok1 and Amr H. Sawalha2,3 ’Division of Rheumatology, Department of Internal Medicine, University Ebook Epigenetics and dermatology: Part 2ure in SSc 1141. MVEC dysfunction leads to a host of changes in the blood vessels, including obliterative vasculopathy, that eventually results in a state of chronic tissue ischemia [3].25212. EPIGENETICS AND SYSTEMIC SCLEROSIS3Role of fibroblasts in SScFibroblasts play an important role in the path Ebook Epigenetics and dermatology: Part 2ogenesis of SSc, especially considering that fibroblasts are the most proximate cell for collagen production. In comparison to normal fibroblasts, SScEbook Epigenetics and dermatology: Part 2
fibroblasts produce more collagen 1151 and are characterized by increased proliferation and decreased apoptosis in vitro 1161. Moreover, SSc fibroblaCHAPTER12Epigenetics and Systemic SclerosisNezdm Altorok1 and Amr H. Sawalha2,3 ’Division of Rheumatology, Department of Internal Medicine, University Ebook Epigenetics and dermatology: Part 2ditionally, fibroblasts play a role in activation of the immune system via production of numerous cytokines and chemokines and upregulation of adhesion and costimulatory molecules. Fibroblasts are frequently detected near small blood vessels surrounded by inflammatory cellular infiltrate in the earl Ebook Epigenetics and dermatology: Part 2y stages of SSc 118]. These observations highlight an important role for fibroblasts in the pathogenesis of SSc that goes beyond collagen production aEbook Epigenetics and dermatology: Part 2
nd expansion of ECM, to involve activation of the immune system.The TGF-p signaling pathway is the most potent stimulus for myofibroblast differentiatCHAPTER12Epigenetics and Systemic SclerosisNezdm Altorok1 and Amr H. Sawalha2,3 ’Division of Rheumatology, Department of Internal Medicine, University Ebook Epigenetics and dermatology: Part 2roblast transformation [19]. Other fibrotic pathways are also important in SSc, such as the Wnt/3-catenin, Hedgehog, and Jagged—Notch signaling pathways. Collagen gene transcription in fibroblasts is modulated by several profibrotic cytokines and transcription factors. Friend leukemia integration-1 Ebook Epigenetics and dermatology: Part 2(Fli-1) is one of the transcription factors that repress expression of collagen [201. Fli-1 is among the transcription factors that are underexpressedEbook Epigenetics and dermatology: Part 2
in SSc fibroblasts. SMAD3 is a profibrotic factor in the TGF-3 downstream signaling cascade [21], whereas SMAD7 is an inhibitory factor that modulateCHAPTER12Epigenetics and Systemic SclerosisNezdm Altorok1 and Amr H. Sawalha2,3 ’Division of Rheumatology, Department of Internal Medicine, University Ebook Epigenetics and dermatology: Part 2ance that favors increased collagen expression and tissue fibrosis.Gọi ngay
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