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Major histocompatibility complex and alveolar epithelial apoptosis in idiopathic pulmonary fibrosis

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by fibroblast expansion, and tissue remodeling. It is considered a multifactorial disease but the possible involved genes are largely unknown. Interestingly, studies regarding the possible role of major histocompatibility complex (MHC) are scanty and show contradictory results. In this study, we evaluated the polymorphisms of the MHC, locus HLA-B, -DRB1, and -DQB1 in a cohort of 75 IPF patients and 95 controls by using PCR and hybridization with sequence-specific oligonucleotide probes. In addition, we examined the effect of bronchoalveolar lavage (BAL) from IPF patients with different MHC haplotypes on alveolar epithelial growth rate by WST-1 cell viability assay and on epithelial apoptosis by flow cytometry and by cleaved caspase-3 in cell homogenates. Three haplotypes were significantly increased in IPF: (1) HLA-B*15-DRB1*0101-DQB1*0501 (OR=10.72, CI=1.43–459.6; pC=0.011); (2) HLA-B*52-DRB1*1402-DQB1*0301 (OR=4.42, CI=1.21–24.1; pC=0.024); and (3) HLA-B*35-DRB1*0407-DQB1*0302 (OR=4.73, CI=1.53–19.5; pC=0.005). BAL from patients with the later haplotype significantly reduced epithelial growth rate (∼30%) and caused epithelial cell apoptosis assayed by cleaved caspase-3 (351.7±16.5 pg/106 cells versus 264±24 from controls, and 274±36.8 and 256.5±10.7 from the other haplotypes; P<0.05), and DNA breaks labeling by flow cytometry (23.7±6.9% versus 3.1±0.7% from controls, and 6.5±0.6% and 7.6±1.2% from the other two haplotypes; P<0.01). These findings suggest that some MHC polymorphisms confer susceptibility to IPF, which might be related with the induction of epithelial cell apoptosis, a critical process in the development of the disease.

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Acknowledgments

This study was supported by a Grant from CONACYT# 43832-M. This work was submitted in partial fulfillment of the requirements to obtain the PhD degree for R.F.V. at Biomedical Sciences, UNAM.

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Authors and Affiliations

  1. Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, CP 14080, México DF, Mexico

    Ramcés Falfán-Valencia, Angel Camarena, Armida Juárez, Carina Becerril, Martha Montaño, José Cisneros, Felipe Mendoza & Moisés Selman

  2. Instituto Nacional de Ciencias Médicas y la Nutrición Salvador Zubirán, Mexico, Mexico

    Julio Granados

  3. Facultad de Ciencias, Universidad Nacional Autónoma de México, Cuernavaca, Mexico

    Annie Pardo

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  1. Ramcés Falfán-Valencia
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Correspondence to Moisés Selman.

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Falfán-Valencia, R., Camarena, A., Juárez, A. et al. Major histocompatibility complex and alveolar epithelial apoptosis in idiopathic pulmonary fibrosis. Hum Genet 118, 235–244 (2005). https://doi.org/10.1007/s00439-005-0035-7

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  • DOI: https://doi.org/10.1007/s00439-005-0035-7

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