Fractalcina/CX3CL1 y su rol en la fisiopatología en esclerosis sistémica

La esclerosis sistémica (ES) es una enfermedad autoinmune del tejido conectivo caracterizada por la presencia de vasculopatía, alteración de la respuesta inmune generando fibrosis en piel y órganos internos. Debido a su alta tasa de mortalidad y la complejidad en el tratamiento, se hace necesario in...

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Autores:
Cordoba Mora, Rodrigo Hernán
Tipo de recurso:
Trabajo de grado de pregrado
Fecha de publicación:
2024
Institución:
Colegio Mayor de Cundinamarca
Repositorio:
Repositorio Colegio Mayor de Cundinamarca
Idioma:
spa
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oai:repositorio.unicolmayor.edu.co:unicolmayor/7057
Acceso en línea:
https://repositorio.unicolmayor.edu.co/handle/unicolmayor/7057
Palabra clave:
Esclerosis sistémica
Autoinmunidad
Vasculopatía
Respuesta inmune
Biomarcadores
Quimiocina
Endotelio
Diagnóstico
Tratamiento
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Derechos Reservados - Universidad Colegio Mayor de Cundinamarca, 2024
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dc.title.spa.fl_str_mv Fractalcina/CX3CL1 y su rol en la fisiopatología en esclerosis sistémica
title Fractalcina/CX3CL1 y su rol en la fisiopatología en esclerosis sistémica
spellingShingle Fractalcina/CX3CL1 y su rol en la fisiopatología en esclerosis sistémica
Esclerosis sistémica
Autoinmunidad
Vasculopatía
Respuesta inmune
Biomarcadores
Quimiocina
Endotelio
Diagnóstico
Tratamiento
title_short Fractalcina/CX3CL1 y su rol en la fisiopatología en esclerosis sistémica
title_full Fractalcina/CX3CL1 y su rol en la fisiopatología en esclerosis sistémica
title_fullStr Fractalcina/CX3CL1 y su rol en la fisiopatología en esclerosis sistémica
title_full_unstemmed Fractalcina/CX3CL1 y su rol en la fisiopatología en esclerosis sistémica
title_sort Fractalcina/CX3CL1 y su rol en la fisiopatología en esclerosis sistémica
dc.creator.fl_str_mv Cordoba Mora, Rodrigo Hernán
dc.contributor.advisor.none.fl_str_mv Cruz Vaquero, Claudia Andrea
Ramírez Santana, Carolina
dc.contributor.author.none.fl_str_mv Cordoba Mora, Rodrigo Hernán
dc.contributor.corporatename.spa.fl_str_mv Universidad Colegio Mayor de Cundinamarca
dc.subject.proposal.spa.fl_str_mv Esclerosis sistémica
Autoinmunidad
Vasculopatía
Respuesta inmune
Biomarcadores
Quimiocina
Endotelio
Diagnóstico
Tratamiento
topic Esclerosis sistémica
Autoinmunidad
Vasculopatía
Respuesta inmune
Biomarcadores
Quimiocina
Endotelio
Diagnóstico
Tratamiento
description La esclerosis sistémica (ES) es una enfermedad autoinmune del tejido conectivo caracterizada por la presencia de vasculopatía, alteración de la respuesta inmune generando fibrosis en piel y órganos internos. Debido a su alta tasa de mortalidad y la complejidad en el tratamiento, se hace necesario intensificar la búsqueda de nuevos biomarcadores que permitan detectar la fase temprana de la enfermedad, facilitando así el diagnóstico temprano y el tratamiento oportuno. En la búsqueda de nuevos biomarcadores se ha propuesto a las quimioquinas como biomarcadores en las enfermedades autoinmunes. Un ejemplo es la Fractalcina/CX3CL, la cual puede actuar como molécula de adhesión en el endotelio inflamado, promoviendo la retención de monocitos y células T cuando está anclada a la membrana. Además, en su forma soluble, induce la migración de monocitos, células asesinas naturales (NK) y células T. Por tal motivo, se ha propuesto la Fractalcina/ CX3CL1 como candidata a biomarcador en ES, debido a su papel es el proceso inflamatorio en las enfermedades autoinmunes (EA), especialmente en la ES. Este proyecto tiene como objetivo identificar y describir Fractalcina/ CX3CL1 como un posible biomarcador predictivo para el diagnóstico de la esclerosis sistémica.
publishDate 2024
dc.date.accessioned.none.fl_str_mv 2024-09-20T13:53:25Z
dc.date.available.none.fl_str_mv 2024-09-20T13:53:25Z
dc.date.issued.none.fl_str_mv 2024-04-19
dc.type.spa.fl_str_mv Trabajo de grado - Pregrado
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dc.relation.references.spa.fl_str_mv Lepri G, Bellando Randone S, Matucci Cerinic M, Guiducci S. Early diagnosis of systemic sclerosis, where do we stand today? Expert Rev Clin Immunol. 2022 Jan 2;18(1):1–3.
Masi AT. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum. 1980 May;23(5):581–90.
Van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 Classification Criteria for Systemic Sclerosis: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative. Arthritis Rheum. 2013 Nov 3;65(11):2737–47.
Fabri M, Hunzelmann N. Differential diagnosis of scleroderma and pseudoscleroderma. JDDG. 2007 Nov;5(11):977–83.
Burbelo PD, Gordon SM, Waldman M, Edison JD, Little DJ, Stitt RS, et al. Autoantibodies are present before the clinical diagnosis of systemic sclerosis. PLoS One. 2019 Mar 26;14(3):e0214202.
Denton CP, Khanna D. Systemic sclerosis. The Lancet. 2017 Oct;390(10103):1685–99.
Sobolewski P, Maślińska M, Wieczorek M, Łagun Z, Malewska A, Roszkiewicz M, et al. Systemic sclerosis – multidisciplinary disease: clinical features and treatment. Rheumatology. 2019 Sep 24;57(4):221–33.
Lepri G, Bellando Randone S, Matucci Cerinic M, Guiducci S. Early diagnosis of systemic sclerosis, where do we stand today? Expert Rev Clin Immunol. 2022 Jan 2;18(1):1–3.
Cutolo M, Soldano S, Smith V. Pathophysiology of systemic sclerosis: current understanding and new insights. Expert Rev Clin Immunol. 2019 Jul 3;15(7):753–64.
van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis. 2013 Nov 3;72(11):1747–55.
Wik L, Nordberg N, Broberg J, Björkesten J, Assarsson E, Henriksson S, et al. Proximity Extension Assay in Combination with Next-Generation Sequencing for High-throughput Proteome-wide Analysis. Molecular & Cellular Proteomics. 2021;20:100168
Aspe Unanue L, González Hermosa MR, Gardeazabal García J. Esclerodermia (esclerosis sistémica). Piel. 2010 May;25(5):252–66.
Fernández-Ávila DG, Bernal-Macías S, Gutiérrez JM, Rincón DN, Rosselli D. Prevalence of systemic sclerosis in Colombia: Data from the National Health Registry 2012–2016. J Scleroderma Relat Disord. 2020 Jun 19;5(2):137–42.
Rodnan GP, Lipinski E, Luksick J. Skin thickness and collagen content in progressive systemic sclerosis and localized scleroderma. Arthritis Rheum. 1979 Feb;22(2):130–40.
ESCLEROSIS SISTÉMICA (ESCLERODERMIA). Consejo General De Colegios Oficiales De Farmaceuticos [Internet]. :5–19. Available from: https://www.cofbadajoz.com/wp-content/uploads/2018/03/ESCLEROSIS-SISTÉMICA.pdf
Thombs BD, Hudson M, Taillefer SS, Baron M. Prevalence and clinical correlates of symptoms of depression in patients with systemic sclerosis. Arthritis Rheum. 2008 Apr 15;59(4):504–9.
Fabri M, Hunzelmann N. Differential diagnosis of scleroderma and pseudoscleroderma. JDDG. 2007 Nov;5(11):977–83.
Colmenares Roldán LM, Velásquez Franco CJ, Mesa Navas MA. Capillaroscopy in systemic sclerosis: A narrative literature review. Revista Colombiana de Reumatología (English Edition). 2016 Oct;23(4):250–8.
HASSAN ML. CONSENSO SOBRE ESCLERODERMIA ACTUALIZACIÓN 2015. 2015.
Rodnan GP, Lipinski E, Luksick J. Skin thickness and collagen content in progressive systemic sclerosis and localized scleroderma. Arthritis Rheum. 1979 Feb;22(2):130–40.
ESCLEROSIS SISTÉMICA (ESCLERODERMIA). Consejo General De Colegios Oficiales De Farmaceuticos. :5–19.
Aspe Unanue L, González Hermosa MR, Gardeazabal García J. Esclerodermia (esclerosis sistémica). Piel. 2010 May;25(5):252–66.
Aspe Unanue L, González Hermosa MR, Gardeazabal García J. Esclerodermia (esclerosis sistémica). Piel. 2010 May;25(5):252–66.
Allanore Y. Esclerodermia sistémica: epidemiología, fisiopatología y clínica. EMC - Aparato Locomotor. 2022 Dec;55(4):1–27.
Allanore Y. Esclerodermia sistémica: epidemiología, fisiopatología y clínica. EMC - Aparato Locomotor. 2022 Dec;55(4):1–27.
Denton CP, Khanna D. Systemic sclerosis. The Lancet. 2017 Oct;390(10103):1685–99.
Greiffo FR, Viteri-Alvarez V, Frankenberger M, Dietel D, Ortega-Gomez A, Lee JS, et al. CX3CR1–fractalkine axis drives kinetic changes of monocytes in fibrotic interstitial lung diseases. European Respiratory Journal. 2020 Feb;55(2):1900460
Thoreau B, Chaigne B, Renaud A, Mouthon L. Pathophysiology of systemic sclerosis. Presse Med. 2021 Apr;50(1):104087.
Hattori M, Yokoyama Y, Hattori T, Motegi S, Amano H, Hatada I, et al. Global <scp>DNA</scp> hypomethylation and hypoxia‐induced expression of the ten eleven translocation ( <scp>TET</scp> ) family, <scp>TET</scp> 1, in scleroderma fibroblasts. Exp Dermatol. 2015 Nov 14;24(11):841–6.
Joven BE, Carreira PE. Síndrome de Raynaud: etiología y manejo. Reumatol Clin. 2008 Mar;4(2):59–66.
Bhattacharyya S, Varga J. Emerging Roles of Innate Immune Signaling and Toll-Like Receptors in Fibrosis and Systemic Sclerosis. Curr Rheumatol Rep. 2015 Jan 22;17(1):2.
Sociedad Cubana de Reumatologíía SE, Grupo Nacional de Reumatologíía (Cuba) G, Avilés del Campo E, Pérez Torres L. Revista cubana de reumatologíía. Vol. 16, Revista Cubana de Reumatología. Sociedad Cubana de Reumatología; 2014. 304–308 p.
Yoshizaki A. Pathogenic roles of B lymphocytes in systemic sclerosis. Immunol Lett. 2018 Mar;195:76–82.
Sonsoles Piera-Velázquez CTDerk y SAJ. PATOGÉNESIS DE LA ESCLEROSIS SISTÉMICA. SISBIB. 2004;Revista Peruana de Reumatología.
Jiménez-Romero ME, Caro-Gómez I. Biomarcadores en el cáncer de próstata. Implicación en la práctica clínica. Rev Mex Urol. 2014 Jul;74(4):226–33.
Giacomelli R, Afeltra A, Alunno A, Bartoloni-Bocci E, Berardicurti O, Bombardieri M, et al. Guidelines for biomarkers in autoimmune rheumatic diseases - evidence based analysis. Autoimmun Rev. 2019 Jan;18(1):93–106.
Goodnow CC, Sprent J, de St Groth BF, Vinuesa CG. Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature. 2005 Jun 2;435(7042):590–7.
Harrington C, Krishnan S, Mack CL, Cravedi P, Assis DN, Levitsky J. Noninvasive biomarkers for the diagnosis and management of autoimmune hepatitis. Hepatology. 2022 Dec 8;76(6):1862–79.
Lee EY, Lee ZH, Song YW. CXCL10 and autoimmune diseases. Autoimmun Rev. 2009 Mar;8(5):379–83.
Antonelli A, Ferri C, Fallahi P, Ferrari SM, Giuggioli D, Colaci M, et al. CXCL10 ( ) and CCL2 ( ) chemokines in systemic sclerosis a longitudinal study. Rheumatology. 2008 Jan 1;47(1):45–9.
Zheng B, Keen KJ, Fritzler MJ, Ryerson CJ, Wilcox P, Whalen BA, et al. Circulating cytokine levels in systemic sclerosis related interstitial lung disease and idiopathic pulmonary fibrosis. Sci Rep. 2023 Apr 24;13(1):6647.
Lande R, Lee EY, Palazzo R, Marinari B, Pietraforte I, Santos GS, et al. CXCL4 assembles DNA into liquid crystalline complexes to amplify TLR9-mediated interferon-α production in systemic sclerosis. Nat Commun. 2019 May 1;10(1):1731.
Silva-Cardoso SC, Tao W, Angiolilli C, Lopes AP, Bekker CPJ, Devaprasad A, et al. CXCL4 Links Inflammation and Fibrosis by Reprogramming Monocyte-Derived Dendritic Cells in vitro. Front Immunol. 2020 Sep 17;11.
Affandi AJ, Carvalheiro T, Ottria A, de Haan JJ, Brans MAD, Brandt MM, et al. CXCL4 drives fibrosis by promoting several key cellular and molecular processes. Cell Rep. 2022 Jan;38(1):110189.
Mendez-Enriquez E, García-Zepeda EA. The multiple faces of CCL13 in immunity and inflammation. Inflammopharmacology. 2013 Dec 12;21(6):397–406.
Yanaba K, Yoshizaki A, Muroi E, Hara T, Ogawa F, Shimizu K, et al. CCL13 is a promising diagnostic marker for systemic sclerosis. British Journal of Dermatology. 2010 Feb;162(2):332–6.
Gambichler T, Yilmaz E, Höxtermann S, Kolios A, Moritz R, Bechara FG, et al. Serum CCL13 levels in patients with systemic sclerosis and controls. British Journal of Dermatology. 2011 Jul;165(1):216–8.
Li L, Dai F, Wang L, Sun Y, Mei L, Ran Y, et al. CCL13 and human diseases. Front Immunol. 2023 Apr 19;14.
Mecca C, Giambanco I, Donato R, Arcuri C. Microglia and Aging: The Role of the TREM2–DAP12 and CX3CL1-CX3CR1 Axes. Int J Mol Sci. 2018 Jan 22;19(1):318.
Arai M, Ikawa Y, Chujo S, Hamaguchi Y, Ishida W, Shirasaki F, et al. Chemokine receptors CCR2 and CX3CR1 regulate skin fibrosis in the mouse model of cytokine-induced systemic sclerosis. J Dermatol Sci. 2013 Mar;69(3):250–8.
Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D, et al. A new class of membrane-bound chemokine with a CX3C motif. Nature. 1997 Feb;385(6617):640–4.
Harrison JK, Fong AlanM, Swain PeterAW, Chen S, Yu YReiA, Salafranca MN, et al. Mutational Analysis of the Fractalkine Chemokine Domain. Journal of Biological Chemistry. 2001 Jun;276(24):21632–41.
Chandrasekar B, Melby PC, Sarau HM, Raveendran M, Perla RP, Marelli-Berg FM, et al. Chemokine-Cytokine Cross-talk. Journal of Biological Chemistry. 2003 Feb;278(7):4675–86.
Mattison HA, Nie H, Gao H, Zhou H, Hong JS, Zhang J. Suppressed pro-inflammatory response of microglia in CX3CR1 knockout mice. J Neuroimmunol. 2013 Apr;257(1–2):110–5.
Haskell CA, Cleary MD, Charo IF. Unique Role of the Chemokine Domain of Fractalkine in Cell Capture. Journal of Biological Chemistry. 2000 Nov;275(44):34183–9.
Pawelec P, Ziemka-Nalecz M, Sypecka J, Zalewska T. The Impact of the CX3CL1/CX3CR1 Axis in Neurological Disorders. Cells. 2020 Oct 13;9(10):2277.
Hoffmann-Vold AM, Weigt SS, Palchevskiy V, Volkmann E, Saggar R, Li N, et al. Augmented concentrations of CX3CL1 are associated with interstitial lung disease in systemic sclerosis. PLoS One. 2018 Nov 20;13(11):e0206545.
Marchesi F, Locatelli M, Solinas G, Erreni M, Allavena P, Mantovani A. Role of CX3CR1/CX3CL1 axis in primary and secondary involvement of the nervous system by cancer. J Neuroimmunol. 2010 Jul;224(1–2):39–44.
Moon SO, Kim W, Sung MJ, Lee S, Kang KP, Kim DH, et al. Resveratrol Suppresses Tumor Necrosis Factor-α-Induced Fractalkine Expression in Endothelial Cells. Mol Pharmacol. 2006 Jul;70(1):112–9.
Dénes Á, Ferenczi S, Halász J, Környei Z, Kovács KJ. Role of CX3CR1 (Fractalkine Receptor) in Brain Damage and Inflammation Induced by Focal Cerebral Ischemia in Mouse. Journal of Cerebral Blood Flow & Metabolism. 2008 Oct 25;28(10):1707–21.
Rosendahl A, Schönborn K, Krieg T. Pathophysiology of systemic sclerosis (scleroderma). Kaohsiung J Med Sci. 2022 Mar 2;38(3):187–95.
Jones BA, Beamer M, Ahmed S. Fractalkine/CX3CL1: A Potential New Target for Inflammatory Diseases. Mol Interv. 2010 Oct 1;10(5):263–70.
Julia V, Staumont-Salle D, Dombrowicz D. Rôle de la fractalkine/CX3CL1 et de son récepteur CX3CR1 dans les pathologies allergiques. médecine/sciences. 2016 Mar 23;32(3):260–6.
Mionnet C, Buatois V, Kanda A, Milcent V, Fleury S, Lair D, et al. CX3CR1 is required for airway inflammation by promoting T helper cell survival and maintenance in inflamed lung. Nat Med. 2010 Nov;16(11):1305–12
S Sato, T-Echigo, Y Hamaguchi, M Yasui, K Takehara. Expresión regulada por aumento de fractalquina/CX 3 CL1 y CX 3 CR1 en pacientes con esclerosis sistémica. BMJ Journals. 2004 Dec 4;
Marasini B, Cossutta R, Selmi C, Pozzi MR, Gardinali M, Massarotti M, et al. Polymorphism of the Fractalkine Receptor CX3CR1 and Systemic Sclerosis-associated Pulmonary Arterial Hypertension. Clin Dev Immunol. 2005;12(4):275–9.
Balabanian K, Foussat A, Dorfmüller P, Durand-Gasselin I, Capel F, Bouchet-Delbos L, et al. CX 3 C Chemokine Fractalkine in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2002 May 15;165(10):1419–25.
Guo L, Lu X, Wang Y, Bao C, Chen S. Elevated levels of soluble fractalkine and increased expression of CX3CR1 in neuropsychiatric systemic lupus erythematosus. Exp Ther Med. 2017 Oct;14(4):3153–8.
QuantikineTM ELISA. Human CX3CL1/Fractalkine Quantikine ELISA Kit. 2021 May.
Luong VH, Utsunomiya A, Chino T, Doanh LH, Matsushita T, Obara T, et al. Inhibition of the Progression of Skin Inflammation, Fibrosis, and Vascular Injury by Blockade of the <scp>CX</scp> 3 <scp>CL</scp> 1/ <scp>CX</scp> 3 <scp>CR</scp> 1 Pathway in Experimental Mouse Models of Systemic Sclerosis. Arthritis & Rheumatology. 2019 Nov 11;71(11):1923–34.
Nanki T, Imai T, Kawai S. Fractalkine/CX3CL1 in rheumatoid arthritis. Mod Rheumatol. 2017 May 4;27(3):392–7.
Lu X. Structure and Function of Ligand CX3CL1 and its Receptor CX3CR1 in Cancer. Curr Med Chem. 2022 Dec;29(41):6228–46.
Greiffo FR, Viteri-Alvarez V, Frankenberger M, Dietel D, Ortega-Gomez A, Lee JS, et al. CX3CR1–fractalkine axis drives kinetic changes of monocytes in fibrotic interstitial lung diseases. European Respiratory Journal. 2020 Feb;55(2):1900460.
Jones B, Koch AE, Ahmed S. Pathological Role of Fractalkine/CX3CL1 in Rheumatic Diseases: A Unique Chemokine with Multiple Functions. Front Immunol. 2012;2.
Hasegawa M. Up regulated expression of fractalkine/CX3CL1 and CX3CR1 in patients with systemic sclerosis. Ann Rheum Dis. 2005 Jan 1;64(1):21–8.
Jones B, Koch AE, Ahmed S. Pathological Role of Fractalkine/CX3CL1 in Rheumatic Diseases: A Unique Chemokine with Multiple Functions. Front Immunol. 2012;2.
Jones B, Koch AE, Ahmed S. Pathological Role of Fractalkine/CX3CL1 in Rheumatic Diseases: A Unique Chemokine with Multiple Functions. Front Immunol. 2012;2.
Guo L, Lu X, Wang Y, Bao C, Chen S. Elevated levels of soluble fractalkine and increased expression of CX3CR1 in neuropsychiatric systemic lupus erythematosus. Exp Ther Med. 2017 Oct;14(4):3153–8.
S Sato, T-Echigo, Y Hamaguchi, M Yasui, K Takehara. Expresión regulada por aumento de fractalquina/CX 3 CL1 y CX 3 CR1 en pacientes con esclerosis sistémica. BMJ Journals. 2004 Dec 4;
Hoffmann-Vold AM, Weigt SS, Palchevskiy V, Volkmann E, Saggar R, Li N, et al. Augmented concentrations of CX3CL1 are associated with interstitial lung disease in systemic sclerosis. PLoS One. 2018 Nov 20;13(11):e0206545.
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spelling Cruz Vaquero, Claudia Andrea09eab99495c2a9b27223da29af7e0200Ramírez Santana, Carolinac2a9afa2411dede95bd37d3aba1e68aaCordoba Mora, Rodrigo Hernán25822b2c9c4ff348869c333783477960Universidad Colegio Mayor de Cundinamarca2024-09-20T13:53:25Z2024-09-20T13:53:25Z2024-04-19https://repositorio.unicolmayor.edu.co/handle/unicolmayor/7057La esclerosis sistémica (ES) es una enfermedad autoinmune del tejido conectivo caracterizada por la presencia de vasculopatía, alteración de la respuesta inmune generando fibrosis en piel y órganos internos. Debido a su alta tasa de mortalidad y la complejidad en el tratamiento, se hace necesario intensificar la búsqueda de nuevos biomarcadores que permitan detectar la fase temprana de la enfermedad, facilitando así el diagnóstico temprano y el tratamiento oportuno. En la búsqueda de nuevos biomarcadores se ha propuesto a las quimioquinas como biomarcadores en las enfermedades autoinmunes. Un ejemplo es la Fractalcina/CX3CL, la cual puede actuar como molécula de adhesión en el endotelio inflamado, promoviendo la retención de monocitos y células T cuando está anclada a la membrana. Además, en su forma soluble, induce la migración de monocitos, células asesinas naturales (NK) y células T. Por tal motivo, se ha propuesto la Fractalcina/ CX3CL1 como candidata a biomarcador en ES, debido a su papel es el proceso inflamatorio en las enfermedades autoinmunes (EA), especialmente en la ES. Este proyecto tiene como objetivo identificar y describir Fractalcina/ CX3CL1 como un posible biomarcador predictivo para el diagnóstico de la esclerosis sistémica.Tabla de contenido Información General 1 1. RESUMEN 2 2. INTRODUCCIÓN 3 3. PLANTEAMIENTO DEL PROBLEMA: 4 4. ANTECEDENTES 6 5. MARCO REFERENCIAL 8 6. CRITERIOS DIAGNÓSTICOS 10 7. TIPOS DE ESCLEROSIS 15 7.1 Esclerosis sistémica limitada15 7.2 Esclerosis sistémica difusa 15 8. MANIFESTACIONES VASCULARES 17 9. MANIFESTACIONES CUTÁNEAS 18 10. FISIOPATOLOGÍA 21 11. FACTORES PREDISPONENTES DE LA ENFERMEDAD 23 12. VASCULOPATÍA25 13. RESPUESTA Y ACTIVACIÓN DEL SISTEMA INMUNE 26 14. PROCESO FIBRÓTICO29 15. TRATAMIENTO 31 16. BIOMARCADORES 32 16.1 Tipos de biomarcadores: 32 16.2 Quimiocinas 33 17. ESTRUCTURA BIOLÓGICA 37 18. EXPRESIÓN CELULAR 39 18.1 Células implicadas en la expresión de CX3CL1 en Enfermedades Autoinmunes (EAI). 39 19. UNIVERSO, POBLACIÓN Y MUESTRA 42 19.1 Tipo de estudio: 42 20. HIPÓTESIS, VARIABLES E INDICADORES 45 21. TÉCNICAS Y PROCEDIMIENTOS 49 22. RESULTADOS 52 23. DISCUSIÓN 72 24. CONCLUSIONES78 Bibliografía 80PregradoBacteriólogo(a) y Laboratorista Clínico98p.application/pdfspaUniversidad Colegio Mayor de CundinamarcaFacultad de Ciencias de la SaludBogotá D.CBacteriología y Laboratorio ClínicoDerechos Reservados - Universidad Colegio Mayor de Cundinamarca, 2024https://creativecommons.org/licenses/by-nc/4.0/info:eu-repo/semantics/closedAccessAtribución-NoComercial 4.0 Internacional (CC BY-NC 4.0)http://purl.org/coar/access_right/c_14cbFractalcina/CX3CL1 y su rol en la fisiopatología en esclerosis sistémicaTrabajo de grado - Pregradohttp://purl.org/coar/resource_type/c_7a1fhttp://purl.org/coar/version/c_970fb48d4fbd8a85Textinfo:eu-repo/semantics/bachelorThesishttps://purl.org/redcol/resource_type/TPinfo:eu-repo/semantics/publishedVersionLepri G, Bellando Randone S, Matucci Cerinic M, Guiducci S. Early diagnosis of systemic sclerosis, where do we stand today? Expert Rev Clin Immunol. 2022 Jan 2;18(1):1–3.Masi AT. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum. 1980 May;23(5):581–90.Van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 Classification Criteria for Systemic Sclerosis: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative. Arthritis Rheum. 2013 Nov 3;65(11):2737–47.Fabri M, Hunzelmann N. Differential diagnosis of scleroderma and pseudoscleroderma. JDDG. 2007 Nov;5(11):977–83.Burbelo PD, Gordon SM, Waldman M, Edison JD, Little DJ, Stitt RS, et al. Autoantibodies are present before the clinical diagnosis of systemic sclerosis. PLoS One. 2019 Mar 26;14(3):e0214202.Denton CP, Khanna D. Systemic sclerosis. The Lancet. 2017 Oct;390(10103):1685–99.Sobolewski P, Maślińska M, Wieczorek M, Łagun Z, Malewska A, Roszkiewicz M, et al. Systemic sclerosis – multidisciplinary disease: clinical features and treatment. Rheumatology. 2019 Sep 24;57(4):221–33.Lepri G, Bellando Randone S, Matucci Cerinic M, Guiducci S. Early diagnosis of systemic sclerosis, where do we stand today? Expert Rev Clin Immunol. 2022 Jan 2;18(1):1–3.Cutolo M, Soldano S, Smith V. Pathophysiology of systemic sclerosis: current understanding and new insights. Expert Rev Clin Immunol. 2019 Jul 3;15(7):753–64.van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis. 2013 Nov 3;72(11):1747–55.Wik L, Nordberg N, Broberg J, Björkesten J, Assarsson E, Henriksson S, et al. Proximity Extension Assay in Combination with Next-Generation Sequencing for High-throughput Proteome-wide Analysis. Molecular & Cellular Proteomics. 2021;20:100168Aspe Unanue L, González Hermosa MR, Gardeazabal García J. Esclerodermia (esclerosis sistémica). Piel. 2010 May;25(5):252–66.Fernández-Ávila DG, Bernal-Macías S, Gutiérrez JM, Rincón DN, Rosselli D. Prevalence of systemic sclerosis in Colombia: Data from the National Health Registry 2012–2016. J Scleroderma Relat Disord. 2020 Jun 19;5(2):137–42.Rodnan GP, Lipinski E, Luksick J. Skin thickness and collagen content in progressive systemic sclerosis and localized scleroderma. Arthritis Rheum. 1979 Feb;22(2):130–40.ESCLEROSIS SISTÉMICA (ESCLERODERMIA). Consejo General De Colegios Oficiales De Farmaceuticos [Internet]. :5–19. Available from: https://www.cofbadajoz.com/wp-content/uploads/2018/03/ESCLEROSIS-SISTÉMICA.pdfThombs BD, Hudson M, Taillefer SS, Baron M. Prevalence and clinical correlates of symptoms of depression in patients with systemic sclerosis. Arthritis Rheum. 2008 Apr 15;59(4):504–9.Fabri M, Hunzelmann N. Differential diagnosis of scleroderma and pseudoscleroderma. JDDG. 2007 Nov;5(11):977–83.Colmenares Roldán LM, Velásquez Franco CJ, Mesa Navas MA. Capillaroscopy in systemic sclerosis: A narrative literature review. Revista Colombiana de Reumatología (English Edition). 2016 Oct;23(4):250–8.HASSAN ML. CONSENSO SOBRE ESCLERODERMIA ACTUALIZACIÓN 2015. 2015.Rodnan GP, Lipinski E, Luksick J. Skin thickness and collagen content in progressive systemic sclerosis and localized scleroderma. Arthritis Rheum. 1979 Feb;22(2):130–40.ESCLEROSIS SISTÉMICA (ESCLERODERMIA). Consejo General De Colegios Oficiales De Farmaceuticos. :5–19.Aspe Unanue L, González Hermosa MR, Gardeazabal García J. Esclerodermia (esclerosis sistémica). Piel. 2010 May;25(5):252–66.Aspe Unanue L, González Hermosa MR, Gardeazabal García J. Esclerodermia (esclerosis sistémica). Piel. 2010 May;25(5):252–66.Allanore Y. Esclerodermia sistémica: epidemiología, fisiopatología y clínica. EMC - Aparato Locomotor. 2022 Dec;55(4):1–27.Allanore Y. Esclerodermia sistémica: epidemiología, fisiopatología y clínica. EMC - Aparato Locomotor. 2022 Dec;55(4):1–27.Denton CP, Khanna D. Systemic sclerosis. The Lancet. 2017 Oct;390(10103):1685–99.Greiffo FR, Viteri-Alvarez V, Frankenberger M, Dietel D, Ortega-Gomez A, Lee JS, et al. CX3CR1–fractalkine axis drives kinetic changes of monocytes in fibrotic interstitial lung diseases. European Respiratory Journal. 2020 Feb;55(2):1900460Thoreau B, Chaigne B, Renaud A, Mouthon L. Pathophysiology of systemic sclerosis. Presse Med. 2021 Apr;50(1):104087.Hattori M, Yokoyama Y, Hattori T, Motegi S, Amano H, Hatada I, et al. Global <scp>DNA</scp> hypomethylation and hypoxia‐induced expression of the ten eleven translocation ( <scp>TET</scp> ) family, <scp>TET</scp> 1, in scleroderma fibroblasts. Exp Dermatol. 2015 Nov 14;24(11):841–6.Joven BE, Carreira PE. Síndrome de Raynaud: etiología y manejo. Reumatol Clin. 2008 Mar;4(2):59–66.Bhattacharyya S, Varga J. Emerging Roles of Innate Immune Signaling and Toll-Like Receptors in Fibrosis and Systemic Sclerosis. Curr Rheumatol Rep. 2015 Jan 22;17(1):2.Sociedad Cubana de Reumatologíía SE, Grupo Nacional de Reumatologíía (Cuba) G, Avilés del Campo E, Pérez Torres L. Revista cubana de reumatologíía. Vol. 16, Revista Cubana de Reumatología. Sociedad Cubana de Reumatología; 2014. 304–308 p.Yoshizaki A. Pathogenic roles of B lymphocytes in systemic sclerosis. Immunol Lett. 2018 Mar;195:76–82.Sonsoles Piera-Velázquez CTDerk y SAJ. PATOGÉNESIS DE LA ESCLEROSIS SISTÉMICA. SISBIB. 2004;Revista Peruana de Reumatología.Jiménez-Romero ME, Caro-Gómez I. Biomarcadores en el cáncer de próstata. Implicación en la práctica clínica. Rev Mex Urol. 2014 Jul;74(4):226–33.Giacomelli R, Afeltra A, Alunno A, Bartoloni-Bocci E, Berardicurti O, Bombardieri M, et al. Guidelines for biomarkers in autoimmune rheumatic diseases - evidence based analysis. Autoimmun Rev. 2019 Jan;18(1):93–106.Goodnow CC, Sprent J, de St Groth BF, Vinuesa CG. Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature. 2005 Jun 2;435(7042):590–7.Harrington C, Krishnan S, Mack CL, Cravedi P, Assis DN, Levitsky J. Noninvasive biomarkers for the diagnosis and management of autoimmune hepatitis. Hepatology. 2022 Dec 8;76(6):1862–79.Lee EY, Lee ZH, Song YW. CXCL10 and autoimmune diseases. Autoimmun Rev. 2009 Mar;8(5):379–83.Antonelli A, Ferri C, Fallahi P, Ferrari SM, Giuggioli D, Colaci M, et al. CXCL10 ( ) and CCL2 ( ) chemokines in systemic sclerosis a longitudinal study. Rheumatology. 2008 Jan 1;47(1):45–9.Zheng B, Keen KJ, Fritzler MJ, Ryerson CJ, Wilcox P, Whalen BA, et al. Circulating cytokine levels in systemic sclerosis related interstitial lung disease and idiopathic pulmonary fibrosis. Sci Rep. 2023 Apr 24;13(1):6647.Lande R, Lee EY, Palazzo R, Marinari B, Pietraforte I, Santos GS, et al. CXCL4 assembles DNA into liquid crystalline complexes to amplify TLR9-mediated interferon-α production in systemic sclerosis. Nat Commun. 2019 May 1;10(1):1731.Silva-Cardoso SC, Tao W, Angiolilli C, Lopes AP, Bekker CPJ, Devaprasad A, et al. CXCL4 Links Inflammation and Fibrosis by Reprogramming Monocyte-Derived Dendritic Cells in vitro. Front Immunol. 2020 Sep 17;11.Affandi AJ, Carvalheiro T, Ottria A, de Haan JJ, Brans MAD, Brandt MM, et al. CXCL4 drives fibrosis by promoting several key cellular and molecular processes. Cell Rep. 2022 Jan;38(1):110189.Mendez-Enriquez E, García-Zepeda EA. The multiple faces of CCL13 in immunity and inflammation. Inflammopharmacology. 2013 Dec 12;21(6):397–406.Yanaba K, Yoshizaki A, Muroi E, Hara T, Ogawa F, Shimizu K, et al. CCL13 is a promising diagnostic marker for systemic sclerosis. British Journal of Dermatology. 2010 Feb;162(2):332–6.Gambichler T, Yilmaz E, Höxtermann S, Kolios A, Moritz R, Bechara FG, et al. Serum CCL13 levels in patients with systemic sclerosis and controls. British Journal of Dermatology. 2011 Jul;165(1):216–8.Li L, Dai F, Wang L, Sun Y, Mei L, Ran Y, et al. CCL13 and human diseases. Front Immunol. 2023 Apr 19;14.Mecca C, Giambanco I, Donato R, Arcuri C. Microglia and Aging: The Role of the TREM2–DAP12 and CX3CL1-CX3CR1 Axes. Int J Mol Sci. 2018 Jan 22;19(1):318.Arai M, Ikawa Y, Chujo S, Hamaguchi Y, Ishida W, Shirasaki F, et al. Chemokine receptors CCR2 and CX3CR1 regulate skin fibrosis in the mouse model of cytokine-induced systemic sclerosis. J Dermatol Sci. 2013 Mar;69(3):250–8.Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D, et al. A new class of membrane-bound chemokine with a CX3C motif. Nature. 1997 Feb;385(6617):640–4.Harrison JK, Fong AlanM, Swain PeterAW, Chen S, Yu YReiA, Salafranca MN, et al. Mutational Analysis of the Fractalkine Chemokine Domain. Journal of Biological Chemistry. 2001 Jun;276(24):21632–41.Chandrasekar B, Melby PC, Sarau HM, Raveendran M, Perla RP, Marelli-Berg FM, et al. Chemokine-Cytokine Cross-talk. Journal of Biological Chemistry. 2003 Feb;278(7):4675–86.Mattison HA, Nie H, Gao H, Zhou H, Hong JS, Zhang J. Suppressed pro-inflammatory response of microglia in CX3CR1 knockout mice. J Neuroimmunol. 2013 Apr;257(1–2):110–5.Haskell CA, Cleary MD, Charo IF. Unique Role of the Chemokine Domain of Fractalkine in Cell Capture. Journal of Biological Chemistry. 2000 Nov;275(44):34183–9.Pawelec P, Ziemka-Nalecz M, Sypecka J, Zalewska T. The Impact of the CX3CL1/CX3CR1 Axis in Neurological Disorders. Cells. 2020 Oct 13;9(10):2277.Hoffmann-Vold AM, Weigt SS, Palchevskiy V, Volkmann E, Saggar R, Li N, et al. Augmented concentrations of CX3CL1 are associated with interstitial lung disease in systemic sclerosis. PLoS One. 2018 Nov 20;13(11):e0206545.Marchesi F, Locatelli M, Solinas G, Erreni M, Allavena P, Mantovani A. Role of CX3CR1/CX3CL1 axis in primary and secondary involvement of the nervous system by cancer. J Neuroimmunol. 2010 Jul;224(1–2):39–44.Moon SO, Kim W, Sung MJ, Lee S, Kang KP, Kim DH, et al. Resveratrol Suppresses Tumor Necrosis Factor-α-Induced Fractalkine Expression in Endothelial Cells. Mol Pharmacol. 2006 Jul;70(1):112–9.Dénes Á, Ferenczi S, Halász J, Környei Z, Kovács KJ. Role of CX3CR1 (Fractalkine Receptor) in Brain Damage and Inflammation Induced by Focal Cerebral Ischemia in Mouse. Journal of Cerebral Blood Flow & Metabolism. 2008 Oct 25;28(10):1707–21.Rosendahl A, Schönborn K, Krieg T. Pathophysiology of systemic sclerosis (scleroderma). Kaohsiung J Med Sci. 2022 Mar 2;38(3):187–95.Jones BA, Beamer M, Ahmed S. Fractalkine/CX3CL1: A Potential New Target for Inflammatory Diseases. Mol Interv. 2010 Oct 1;10(5):263–70.Julia V, Staumont-Salle D, Dombrowicz D. Rôle de la fractalkine/CX3CL1 et de son récepteur CX3CR1 dans les pathologies allergiques. médecine/sciences. 2016 Mar 23;32(3):260–6.Mionnet C, Buatois V, Kanda A, Milcent V, Fleury S, Lair D, et al. CX3CR1 is required for airway inflammation by promoting T helper cell survival and maintenance in inflamed lung. Nat Med. 2010 Nov;16(11):1305–12S Sato, T-Echigo, Y Hamaguchi, M Yasui, K Takehara. Expresión regulada por aumento de fractalquina/CX 3 CL1 y CX 3 CR1 en pacientes con esclerosis sistémica. BMJ Journals. 2004 Dec 4;Marasini B, Cossutta R, Selmi C, Pozzi MR, Gardinali M, Massarotti M, et al. Polymorphism of the Fractalkine Receptor CX3CR1 and Systemic Sclerosis-associated Pulmonary Arterial Hypertension. Clin Dev Immunol. 2005;12(4):275–9.Balabanian K, Foussat A, Dorfmüller P, Durand-Gasselin I, Capel F, Bouchet-Delbos L, et al. CX 3 C Chemokine Fractalkine in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med. 2002 May 15;165(10):1419–25.Guo L, Lu X, Wang Y, Bao C, Chen S. Elevated levels of soluble fractalkine and increased expression of CX3CR1 in neuropsychiatric systemic lupus erythematosus. Exp Ther Med. 2017 Oct;14(4):3153–8.QuantikineTM ELISA. Human CX3CL1/Fractalkine Quantikine ELISA Kit. 2021 May.Luong VH, Utsunomiya A, Chino T, Doanh LH, Matsushita T, Obara T, et al. Inhibition of the Progression of Skin Inflammation, Fibrosis, and Vascular Injury by Blockade of the <scp>CX</scp> 3 <scp>CL</scp> 1/ <scp>CX</scp> 3 <scp>CR</scp> 1 Pathway in Experimental Mouse Models of Systemic Sclerosis. Arthritis & Rheumatology. 2019 Nov 11;71(11):1923–34.Nanki T, Imai T, Kawai S. Fractalkine/CX3CL1 in rheumatoid arthritis. Mod Rheumatol. 2017 May 4;27(3):392–7.Lu X. Structure and Function of Ligand CX3CL1 and its Receptor CX3CR1 in Cancer. Curr Med Chem. 2022 Dec;29(41):6228–46.Greiffo FR, Viteri-Alvarez V, Frankenberger M, Dietel D, Ortega-Gomez A, Lee JS, et al. CX3CR1–fractalkine axis drives kinetic changes of monocytes in fibrotic interstitial lung diseases. European Respiratory Journal. 2020 Feb;55(2):1900460.Jones B, Koch AE, Ahmed S. Pathological Role of Fractalkine/CX3CL1 in Rheumatic Diseases: A Unique Chemokine with Multiple Functions. Front Immunol. 2012;2.Hasegawa M. Up regulated expression of fractalkine/CX3CL1 and CX3CR1 in patients with systemic sclerosis. Ann Rheum Dis. 2005 Jan 1;64(1):21–8.Jones B, Koch AE, Ahmed S. Pathological Role of Fractalkine/CX3CL1 in Rheumatic Diseases: A Unique Chemokine with Multiple Functions. Front Immunol. 2012;2.Jones B, Koch AE, Ahmed S. Pathological Role of Fractalkine/CX3CL1 in Rheumatic Diseases: A Unique Chemokine with Multiple Functions. Front Immunol. 2012;2.Guo L, Lu X, Wang Y, Bao C, Chen S. Elevated levels of soluble fractalkine and increased expression of CX3CR1 in neuropsychiatric systemic lupus erythematosus. Exp Ther Med. 2017 Oct;14(4):3153–8.S Sato, T-Echigo, Y Hamaguchi, M Yasui, K Takehara. Expresión regulada por aumento de fractalquina/CX 3 CL1 y CX 3 CR1 en pacientes con esclerosis sistémica. BMJ Journals. 2004 Dec 4;Hoffmann-Vold AM, Weigt SS, Palchevskiy V, Volkmann E, Saggar R, Li N, et al. Augmented concentrations of CX3CL1 are associated with interstitial lung disease in systemic sclerosis. PLoS One. 2018 Nov 20;13(11):e0206545.Esclerosis sistémicaAutoinmunidadVasculopatíaRespuesta inmuneBiomarcadoresQuimiocinaEndotelioDiagnósticoTratamientoORIGINALENTREGA DOCUMENTO FINAL TESIS.pdfENTREGA DOCUMENTO FINAL TESIS.pdfapplication/pdf1126943https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/7057/1/ENTREGA%20DOCUMENTO%20FINAL%20TESIS.pdfdafcfb1275678d45d80fb8cc15a2c659MD51open accessCARTA DERECHOS DE AUTOR IP 2024.docx (13).pdfCARTA DERECHOS DE AUTOR IP 2024.docx (13).pdfapplication/pdf104537https://repositorio.unicolmayor.edu.co/bitstream/unicolmayor/7057/2/CARTA%20DERECHOS%20DE%20AUTOR%20IP%202024.docx%20%2813%29.pdf016f7917a8fe8072faaa328cb6e50f3bMD52metadata only accessFORMATO IDENTIFICACIÓN TRABAJOS DE GRADO (1) (5).pdfFORMATO IDENTIFICACIÓN TRABAJOS DE GRADO (1) 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Unicolmayorrepositorio@unicolmayor.edu.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