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Asociación de los alelos hla DRB1-DQB1 con la infección, persistencia, depuración y reinfección de Chlamydia trachomatis
dc.rights.license | Reconocimiento 4.0 Internacional |
dc.contributor.advisor | Camargo Pinzon, Sandra Milena |
dc.contributor.advisor | Patarroyo Gutiérrez, Manuel Alfonso |
dc.contributor.author | Pedraza Garcia, Leidy Adriana |
dc.date.accessioned | 2022-09-06T14:35:52Z |
dc.date.available | 2022-09-06T14:35:52Z |
dc.date.issued | 2011-02-02 |
dc.identifier.uri | https://repositorio.unal.edu.co/handle/unal/82255 |
dc.description | ilustraciones, graficas |
dc.description.abstract | Las infecciones por Clamydia trachomatis (Ct) se encuentran dentro de las más comunes transmitidas sexualmente y de mayor impacto en la salud pública; la tasa de infección bacteriana descrita para este microorganismo es variable según según la región geográfica y la población de estudio. En los ultimos años se han desarrollado estudios que permiten ampliar la información sobre efectos de los alelos HLA en el curso clínico de las infecciones por Ct; algunos de ellos han permitido establecer la relación directa entre la enfermedad pélvica inflamatoria (EPI) con el HLA-A31 y la presencia de Ct. A su vez, se ha encontrado que alelos como DQA1*0401 y DQB1*0402 presentan una asociación significativa y al mismo tiempo una alta prevalencia en infecciones por Ct. En algunas poblaciones de mujeres se encontró la presencia de alelos DRB1 y DQB1 y una relación directa con la presencia de Ct y la infertilidad tubárica. Las infecciones causadas por Ct y su interacción con el sistema inmune aún son tema de estudio, uno de los métodos que permite el análisis esta interacción son los modelos murinos. Algunos estudios en estos modelos han permitido demostrar que los linfocitos T CD8+ son indispensables en la resolución de las infecciones por Ct; no obstante, los linfocitos T CD4+ y los alelos HLA clase II han sido asociados con la respuesta inmune frente al patógeno. Diversas hipótesis han comprobado que las células epiteliales infectadas pueden presentar conjuntos alélicos del Complejo Mayor de Histocompatibilidad (CMH) clase II superpuestos, promoviendo así la inmunidad protectora hacia Ct. Es así como conocer los genes de los antígenos leucocitarios humanos (HLA) que se relacionan con patologías derivadas de las infecciones por Ct, permite evaluar la respuesta inmune de los hospederos. Algunos análisis realizados en poblaciones de adolescentes mostraron que existen variantes alélicas que se relacionan con la presencia de Ct; sin embargo, las asociaciones entre los alelos HLA-II y las infecciones por Ct han sido pobremente exploradas. En este contexto, el objetivo de este estudio fue determinar el efecto de los alelos y haplotipos HLA DRB1-DQB1 6 sobre el resultado de la infección, persistencia, depuración y reinfección por Ct en una cohorte de mujeres colombianas. Las muestas de este estudio corresponden a una cohorte bidireccional (prospectiva y retrospectiva); para el análisis prospectivo, se contó con muestras cervicales recolectadas entre los años 2007 y 2010 en centros hospitalarios de tres ciudades colombianas: Hospital San Juan Bautista en la ciudad de Chaparral en el departamento del Tolima; el Nuevo Hospital San Rafael en Girardot en Cundinamarca y el Hospital de Engativá Nivel II, en Bogotá, capital de Colombia; el objetivo de ese estudio fue determinar la historia natural de la infección por el virus de papiloma humano (VPH). Para desarrollar el presente estudio, se establecieron como criterios de inclusión la disponibilidad de la muestra cervical para el análisis de HLA- DRB1 y DQB1, mujeres que contaran con al menos cuatro seguimientos (visitas) y una periodicidad entre las visitas de 6 meses (± 3 meses), con el fin de determinar los efectos de los alelos y haplotipos HLA relacionados con los distintos eventos promovidos por Ct. Las muestras que cumplieron con los criterios de inclusión fueron sometidas a detección de Ct, ésta se llevó a cabo mediante reacción en cadena de la polimerasa (PCR), con sets de cebadores dirigidos hacia el ORF2 del plásmido críptico de Ct, amplificando los cebadores KL5/KL6 un fragmento de 350 pb y los cebadores KL1/KL2 un fragmento de 241 pb. La tipificación de los alelos HLA se realizó por NGS (de la sigla en inglés, Next Generation Sequencing) a partir de los exones 2 y 3 de los loci DRB1-DQB1 (resolución 3x) a través de la plataforma Illumina MiSeq. Como análsis adicional, a través del uso de herramientas inmunoinformáticas, se predijeron péptidos de proteínas derivadas de las serovariantes de Ct, seleccionadas para la evaluación de péptidos con alta actividad de unión a los alelos HLA-DRB1 y DQB1. Modelos proporcionales de Cox se llevaron a cabo con el fin de evaluar la relación alelos y haplotipos HLA-DRB1 y DQB1 y el desenlace de las infecciones por Ct; estos modelos fueron ajustardos por variables sociodemográficas y factores de 7 riesgo. Esto permitió establecer la probabilidad de desarrollar los distintos eventos presentados por Ct en función del tiempo y sus coeficientes se expresaron como tasa de riesgo (HR, de la sigla en inglés Hazard ratio), aquellos valores por debajo de 1 se interpretaron como una menor probabilidad de ocurrencia del evento, mientras que los valores por encima de 1 se asociaron con una mayor probabilidad de ocurrencia del evento. Adicionalmente, se estimó el supuesto de riesgos proporcionales con tests basados en los residuos de Schoenfeld, cuando no se cumplieron los supuestos de proporcionalidad, se corrieron modelos paramétricos (Lognormal, Log-logistic, Weibull y Gompertz), los valores por debajo de 1 se relacionaban con una ocurrencia mas temprana del evento, mientras que los coeficientes por encima de 1 indicaban una ocurrencia tardía del evento. Un total de 262 mujeres se incluyeron en el análisis retrospectivo, la media de edad fue de 41,7 años (DE= 23,1), un 29,8% (n=78) de las mujeres iniciaron el estudio con infección por Ct y un 8,9% presentaron al inicio del estudio alguna anormalidad cervical reportada por la citología. En cuanto a los alelos HLA-DRB1, se identificaron dieciséis alelos que presentan un efecto varible sobre el desenlace de las infecciones por Ct. Se observó que DRB1*08:02:01G y DRB1*12:01:01G se relacionaron con eventos que promueven la infección. Solo se encontró el alelo DQB1 *05:03:01G relacionado con eventos de depuración/persistencia para HLA-DQB1. Los sujetos homocigotos para HLA-DRB1 se asociaron a eventos con menor probabilidad de depuración y una aparición temprana de la persistencia. En cuanto a los haplotipos HLA DRB1-DQB1, se identificaron 47 con asociaciones relacionados con los eventos de Ct. Se encontraron 17 haplotipos que favorencían los eventos de infección (probabilidad ó una ocurrencia temprana); 11 haplotipos se asociaron con una ocurrencia tardía de los eventos de infección. Para depuración, 3 haplotipos favorencían su ocurrencia temprana, mientras que 1 presentó menor probabilidad. En cuanto a la reinfección, se relacionaron 8 haplotipos con un un efecto favorable (mayor probabilidad u ocurrencia temprana). Finalmente, se encontraron 9 haplotipos que presentaban una asociación a más de un evento. 8 Como resultado adicional, se realizó la predicción de epítopes con fuerte unión predicha a alelos HLA-DRB1-DQB1. Los resultados mostraron la predicción de 109 pétidos, de los cuales 27 podrían estar asociados a inmunidad protectora frente a Ct; aquellos derivados de las proteínas OMP y PMP exhibieron regiones con doble potencial para ser un epítope de células T o B. Gran parte de las infecciones por Ct cursan de forma asintomática, por lo que estudios epidemiológicos aportan al conocimiento del impacto de las Infecciones de Transmisión Sexual (ITS) en la salud sexual femenina. Aquí describimos por primera vez los alelos y haplotipos HLA-DRB1 y DQB1 relacionados con la resolución de las infecciones por Ct y los péptidos potencialmente involucrados en la respuesta inmune del hospedero. La información obtenida proporciona datos de base para el futuro desarrollo de medidas de promoción y prevención eficaces contra las infecciones por Ct. (Texto tomado de la funte) |
dc.description.abstract | HLA class II (HLA-II) genes’ polymorphism influences the immune response to Chlamydia trachomatis (Ct), it is considered a sexually transmitted infection. However, associations between HLA-II alleles and Ct-infection have been little explored in humans; this study was thus aimed at determining HLA-DRB1-DQB1 alleles/haplotypes’ effect on Ct-infection outcome in a cohort of Colombian women. Cervical sample DNA was used as template for detecting Ct by PCR and typing HLA-DRB1-DQB1 alleles/haplotypes by Illumina MiSeq sequencing. Survival models were adjusted for identifying the alleles/haplotypes’ effect on Ct-outcome; bioinformatics tools were used for predicting secreted bacterial protein T- and B-cell epitopes. Sixteen HLA-DRB1 alleles having a significant effect on Ct-outcome were identified in the 262 women analysed. DRB1*08:02:01G and DRB1*12:01:01G were related to infection-promoting events. Only the DQB1*05:03:01G allele related to clearance/persistence events was found for HLA-DQB1. HLA-DRB1 allele homozygous women were associated with events having a lower probability of clearance and/or early occurrence of persistence. Twentyseven peptides predicted in silico were associated with protective immunity against Ct; outer membrane and polymorphic membrane protein-derived peptides had regions having dual potential for being T- or B-cell epitopes. This article describes HLA-DRB1-DQB1 alleles/haplotypes related to Ct-infection resolution and the peptides predicted in silico which might probably be involved in host immune response. The data provides base information for developing future studies leading to the development of effective prevention measures against Ct-infection. |
dc.format.extent | 137 páginas |
dc.format.mimetype | application/pdf |
dc.language.iso | spa |
dc.publisher | Universidad Nacional de Colombia |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ |
dc.subject.ddc | 610 - Medicina y salud::613 - Salud y seguridad personal |
dc.subject.other | Alelos |
dc.subject.other | Alleles |
dc.subject.other | Haplotipos |
dc.subject.other | Haplotypes |
dc.title | Asociación de los alelos hla DRB1-DQB1 con la infección, persistencia, depuración y reinfección de Chlamydia trachomatis |
dc.type | Trabajo de grado - Maestría |
dc.type.driver | info:eu-repo/semantics/masterThesis |
dc.type.version | info:eu-repo/semantics/acceptedVersion |
dc.publisher.program | Bogotá - Ciencias - Maestría en Ciencias - Microbiología |
dc.contributor.researchgroup | Biología Molecular e InmunologíaFundación Instituto de Inmunología de Colombia |
dc.description.degreelevel | Maestría |
dc.description.degreename | Magíster en Ciencias - Microbiología |
dc.description.researcharea | Epidemiología Molecular |
dc.identifier.instname | Universidad Nacional de Colombia |
dc.identifier.reponame | Repositorio Institucional Universidad Nacional de Colombia |
dc.identifier.repourl | https://repositorio.unal.edu.co/ |
dc.publisher.department | Departamento de Geociencias |
dc.publisher.faculty | Facultad de Ciencias |
dc.publisher.place | Bogotá, Colombia |
dc.publisher.branch | Universidad Nacional de Colombia - Sede Bogotá |
dc.relation.indexed | RedCol |
dc.relation.indexed | LaReferencia |
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dc.rights.accessrights | info:eu-repo/semantics/openAccess |
dc.subject.proposal | Chlamydia trachomatis |
dc.subject.proposal | Infecciones de transmisión sexual |
dc.subject.proposal | HLA DRB1-DQB1 |
dc.subject.proposal | Secuenciación de nueva generación |
dc.subject.proposal | Predicción de epítopes. |
dc.subject.proposal | Chlamydia trachomatis |
dc.subject.proposal | Sexually transmitted infections |
dc.subject.proposal | Next-generation sequencing |
dc.subject.proposal | Epitope prediction |
dc.title.translated | Association of hld DRB1-DQB1 alleles with infecction, persistence, depuration and reinfection of Chlamydia trachomatis |
dc.type.coar | http://purl.org/coar/resource_type/c_bdcc |
dc.type.coarversion | http://purl.org/coar/version/c_ab4af688f83e57aa |
dc.type.content | DataPaper |
dc.type.content | Text |
dc.type.redcol | http://purl.org/redcol/resource_type/TM |
oaire.accessrights | http://purl.org/coar/access_right/c_abf2 |
oaire.fundername | Instituto de Inmunología de Colombia (FIDIC) |
dcterms.audience.professionaldevelopment | Estudiantes |
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