Análisis de la asociación entre alelos HLA clase II y leucemia en población mestiza venezolana. Potenciales implicaciones patogénicas

• Autores: Miriam del Carmen Echeverría Velásquez
• Directores de la Tesis: Sergio Rivera Pirela (dir. tes.), Melchor Álvarez de Mon Soto (dir. tes.)
• Lectura: En la Universidad de Alcalá ( España ) en 2012
• Idioma: español
• Tribunal Calificador de la Tesis: Agustín Albillos Martínez (presid.), David Díaz Martín (secret.), Luis Berlanga González (voc.), M. Leticia Muñoz Zamarrón (voc.), María Kiriakidis Longhi (voc.)
• Materias:
  • Ciencias médicas
    • Patología
      • Inmunopatología
• Enlaces
  • Tesis en acceso abierto en:  e_Buah  TESEO 
• Resumen
  • español

    De este trabajo traslacional de investigación de la asociación de alelo HLA clase II con LLA y LMC en población mestiza venezolana se concluye que: Existen asociaciones positivas entre los alelos DQB1*04*, dpa1*01:07, *01:08, *01:06 con la LLA y los alelos DRB1*14, DPA1*02:01 con la LMC. Las asociaciones alélicas de HLA clase II encontradas en la LLA y LMC son diferentes. La frecuencia alélica del DRB1*13 en la población venezolana no inmigrante reciente demuestra un elevado nivel de mestizaje con presencia de genes caucásicos, afrodescendiente e indígenas. El patrón de positividad de respuesta serológica IgM a adenovirus en pacientes con LLA es similar al encontrado en los controles sanos y, por el contrario fue negativo en la mayoría de los enfermos con LMC. La utilización de alelos de HLA DRB*13 y 14 relacionados con la respuesta a adenovirus es diferente en pacientes con LMC y en la población control. El patrón de respuesta del compartimento linfocitario T a antígenos del adenovirus es distinta en pacientes con LMC y controles. Tomados en conjunto, estos resultados indican, que existen factores genéticos del sistema HLA asociados a la LLA y LMC. Además, el patrón diferente de utilización de estos genes y la respuesta al adenovirus, sugieren que los mecanismos celulares implicados en la patogenia de ambas entidades, son diferentes.

  • English

    Multiple and varied mechanisms have been proposed by several authors as potential contributors in the pathogenesis of leukemia. The molecules of the MHC (major histocompatibility complex) may be associated with the development of leukemia through molecular mimicry between HLA molecules and infectious agents, modifying the structure of HLA molecules, HLA molecules as receptors, deficiencies in the immune response, deficiencies of HLA class III or failure in the selection of T cells with a receptor (TCR) particularly during the positive or negative selection in the thymus among others. Therefore, the objective of this study was to characterize the HLA class II alleles in patients who developed acute lymphoid leukemia (ALL) and chronic myeloid leukemia (CML) in a mestizo population from Venezuela to determine allelic frequencies in each of these groups, distribution and characteristics, and possible associations positive and/or negative HLA class II alleles with leukemia and their implications for disease pathogenesis. A group of 95 patients, adults and children with symptoms characteristic of leukemia, regardless of sex and aged between 7 months and 78 years, were selected and compared with 48 healthy subjects mestizos, with at least three generations born in Venezuela, without leukemia or other illnesses that could alter the immune response. We used peripheral blood samples with EDTA preserved for DNA extraction and molecular study was performed regions of HLA class II DRB1*, DQB1*, DPA1* and DPB1 * amplifying the DNA with PCR specific primers. Antigen specific humoral responses were analyzed by indirect ELISA and cellular responses included the mixed lymphocyte culture and "in vitro" lymphocytes proliferation against the purified antigen. The results were analyzed by the Arlequin statistical program and Chi-square test. In this sample, positive associations were observed between DQB1*04, DPA1*01:07, 1:08 and 1:06* with ALL. The DRB1*13 allele, characteristic of the Venezuelan mestizos population, was negatively associated with ALL. DRB1*14 alleles, DPA1*01:03, *2:01 are positively associated with CML in this population. The different patterns of association between ALL and CML with HLA class II, is this population, suggesting differences in the pathogenesis of both diseases. In ALL we would be a failure in the absence of antigen presentation by DRB1*13 allele in these patients, which would act as a protective antigen in the healthy population. In CML, the pathogenesis would be associated, however, with the presence of HLA-DRB1*14, perhaps a peptide sequence mimicking possibly adenovirus, judging from the observed differences in the cellular and serological responses of these patients to adenoviral peptides. CML patients were predominantly serologically negative to Adenovirus and showed a generation of CD8+ T cells both in culture and in mixed lymphocyte proliferation against peptide sequence adenoviral LLERRRA. The presence of the association HLA-DRB1*14 and CML cell behavior and these patients versus adenoviral stimulus may be related to the pathogenesis of the disease.