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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Asociación HLA y artritis reumatoidea juvenil. En busca de las bases moleculares dependiente del MHC

Garavito de Egea, Gloria 21 April 2004 (has links)
Artritis reumatoidea Juvenil (ARJ) es una enfermedad inflamatoria crónica, autoinmune que afecta a mas de una articulación en lugar y numero. Es una de las enfermedades más comunes en la consulta pediátrica reumatológica y una de las menos estudiadas desde el punto de vista inmunogenetico. En la literatura se ha reportado varias asociaciones de (HLA) Antigenos de Leucocitos Humanos y ARJ con diferentes grupos étnicos, sobre todo con los antigenos HLA clase II: HLA-DR1 y DR4 asociándolos con el subgrupo clínico poliarticularLo contrario a la arthritis reumatoidea del adulto, la ARJ presenta variante clinicas el cual la hace mas interesante desde el punto de vista genetico (fenotipo). Desde el punto de vista patogénesis se han encontrado varios posibles factores que podrían estar en parte, determinados por alteraciones a nivel trimolecular compuesto por un antigeno putativo, el receptor del linfocito T CD4+ y las moléculas HLA.Este estudio se realizo en un grupo de mestizos Colombianos el cual contiene una mezcla génica de amerindio, europea y africana que padecían de ARJ. Se estudio la asociación de los antigenos de leucocitos humanos HLA-DRB1 y HLA -DQB1 en 65 pacientes con ARJ y 65 controles sanos de Colombia En resumen, en este estudio lo hallazgos encontrados fueron la presencia de los alelos HLADRB1*1104 y DRB1*1602 asociados como marcadores de susceptibilidad y los alelos HLA-DRB1*1501 y HLA DRB1*1402 se comportaron como alelos asociados con protección. Al comparar las asociaciones entre alelos y los diferentes subgrupos clínicos se encontró asociación entre ARJ oligoarticular con HLA-DRB1* 1104, ARJ poliarticular se asoció con el alelo HLA-DRB1* 0404 y en el grupo sistémico, el alelo más expresado fue el HLA-DRB1*1602. La presencia de Factor Reumatoide estuvo asociado con los alelos HLA-DRB1*0407 y HLA-DRB1*1302. En el grupo de pacientes con ANA+ solo hubo significancia estadística para el HLA-DRB1* 0701. El subgrupo poliarticular mostró asociación con la secuencia aminoacidica 70 QRRAA74 el cual incluye los alelos HLA DRB1*04, 01 y 1402. Con relación a la asociación haplotipos y subgrupos clínicos, se destacan dos nuevos hallazgos de interés: ARJ oligoarticular se asoció con el haplotipo cacausoide DRB1*1104, DQB1*0301, y el haplotipo amerindio DRB1*1602, DQB1*0602, con AR sistémico. Es de resaltar que le alelos DRB1 de estos dos haplotipos comparten el epitope 70 DRRAA 74. La información obtenida en nuestros pacientes mestizos colombianos son relevante s e importantes por que desde el punto de vista molecular a nivel de presentación antigénica el aminoácido 70 en el motivo 67-73 podría estar activando las células TH1 o TH2 el cual estaría comprometida en la patogénesis de la enfermedad.Nuestros resultados sugieren que los estudios de asociación y susceptibilidad con enfermedades llevados a cabo en poblaciones mestizas, deben considerar la carga genética mixta de estos grupos, étnicos con el objeto de evitar factores de estratificación genética. Nuestros estudios muestran que utilizando técnicas de alta resolución para la tipificación de los alelos HLA-DRB1 y DQB1 serian de gran información para la detección de epitopes específicos de los alelos HLA DRB1 el cual estarían participando no solo en la susceptibilidad a desarrollar ARJ en estos pacientes mestizos, sino también contribuyen en la expresión clínica de la enfermedad. / Juvenile rheumatoid arthritis is the most prevalent pediatric rheumatic diagnosis among children. The term designates a group of diseases that have in common chronic idiopathic inflammation of one or more joints. Substantial evidence points to an autoimmune pathogenesisThe clinical features are paralleled by immunogenetic characteristics that have been found to involve primarily, the major histocompatibility complex (MHC). There are over 50 series reporting HLA associations in JRA. The class II genes, HLA-DR1 and HLA-DR4, have been reported to increase risk for polyarticular JRA in many populations. Contrary to JRA the adult rheumatoid arthritis (RA), JRA has certain clinical variants which make it more interesting from the genetic point of view (phenotypes). In its pathogenesis several factors have been identified, which as a whole would explain the onset and the perpetuation of the inflammatory response affecting joints and nearby tissue as well as its imminent destruction given no control of it as in the case in other autoimmune diseases. The disease pathogenesis can be determined by alterations at the trimolecular level formed by a putative antigen the lymphocyte T receptor and the MHC.We studied the association of human leukocyte antigen HLA-DRB1 and HLA-DQB1 alleles and HLA haplotypes with juvenile rheumatoid arthritis in 65 patients and 65 controls from Colombia. The distribution of these alleles was examined in a group of Colombian mestizo children (genetic admixture of Amerindians, Europeans and Africans) suffering from clinically distinct JRA subsets in order Two alleles were associated with protection, HLA-DRB1*1501and HLA-DRB1*1402. HLA-DRB1*1602 was associated with susceptibility for systemic JRA and HLA-DRB1*1104 for pauciarticular JRA. The relationship between some HLA-DRB1 alleles and clinical features was also compared. The presence of rheumatic factor was associated with the alleles HLA-DRB1*0407 and HLA-DRB1*1302. There was also an association between HLA-DRB1*0701 with expressing ANA+. We found that in the expressed most commonly. In the polyarticular group, the alleles most frequently expressed were HLA-DRB1*0404. It is important to highlight that all the alleles linked to susceptibility share the Asp amino acid in position 70, and those shown as protection markers have Val in the same position.Amino acid sequences at residues 70-74 of DRB1 chain shared by HLA-DRB1 alleles (shared epítope) were also informative. The polyarticular JRA subset revealed association with 70QRRAA74, which includes HLA-DRB1*04, 01, and 70DRRAA74, which includes DRB1*1601, 1602, 1101, and 1104. Two new findings of interest were the association of the haplotypes DRB1*1104, DQB1*0301 with pauciarticular JRA and DRB1*1602, DQB1*0301 association with systemic JRA. The DRB1 alleles of these two haplotypes share the epítope 70DRAA74 and were associated with both the pauciarticular and the systemic subset of JRA. Our results suggest that studies of disease susceptibility in populations of admixed genetic background should take into account the contribution of different ethnic groups or nationalities in the recruitments of controls and patients studied in order to rule our genetic stratification.The information obtained from our findings in our series of Colombian patients are relevant and important because from the molecular point of view, at an antigenic presentation level, the amino acid in position 70 in the motif 67 to 73, at HLA molecule level, could activate TH1 or TH2 cells, which would be compromised in the immunopathology of this entity . Other genetic or/and environmental factors linked to these molecular characteristics expressed at the level of the HLA molecule and compromised in the antigenic response could interact and its result would be influencing the development and the expression of JRA In conclusion, our results demonstrated that the use of high-resolution typing for HLA-DRB1 and DQB1 alleles were informative for detecting specific epitopes of the HLA-DRB1 alleles to produce either protection from JRA susceptibility for pauciarticular or systemic subsets in Colombian mestizos.

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