MICA polymorphisms and decreased expression of the MICA receptor NKG2D contribute to idiopathic pulmonary fibrosis susceptibility.
Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disorder of unknown etiology. IPF is likely the result of complex interrelationships between environmental and host factors, although the genetic risk factors are presently uncertain. Because we have found that some MHC polymorphisms confer susceptibility to IPF, in the present study we aimed to evaluate the role of the MHC class I chain-related gene A (MICA) in the risk of developing the disease. MICA molecular typing was done by reference strand mediated conformation analysis in a cohort of 80 IPF patients and 201 controls. In addition, the lung cellular source of the protein was examined by immunohistochemistry, the expression of the MICA receptor NKG2D in lung cells by flow cytometry and soluble MICA by ELISA. A significant increase of MICA*001 was observed in the IPF cohort (OR = 2.91, 95% CI = 1.04-8.25; pC = 0.03). Likewise, the frequency of the MICA*001/*00201 genotype was significantly increased in patients with IPF compared with the healthy controls (OR = 4.72, 95% CI = 1.15-22.51; pC = 0.01). Strong immunoreactive MICA staining was localized in alveolar epithelial cells and fibroblasts from IPF lungs while control lungs were negative. Soluble MICA was detected in 35% of IPF patients compared with 12% of control subjects (P = 0.0007). The expression of NKG2D was significantly decreased in gammadelta T cells and natural killer cells obtained from IPF lungs. These findings indicate that MICA polymorphisms and abnormal expression of the MICA receptor NKG2D might contribute to IPF susceptibility.
Aquino-Galvez
Arnoldo
A
Instituto Nacional de Enfermedades Respiratorias, Ismael Cosío Villegas, Mexico DF, Mexico.
Pérez-Rodríguez
Martha
M
Camarena
Angel
A
Falfan-Valencia
Ramces
R
Ruiz
Víctor
V
Montaño
Martha
M
Barrera
Lourdes
L
Sada-Ovalle
Isabel
I
Ramírez
Remedios
R
Granados
Julio
J
Pardo
Annie
A
Selman
Moisés
M
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D015235:HLA-B Antigens / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000097:blood / Q000235:genetics*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics*; D007694:Killer Cells, Natural / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D017422:Sequence Analysis, DNA; D016176:T-Lymphocyte Subsets / Q000378:metabolism
D015235:HLA-B Antigens; D015395:Histocompatibility Antigens Class I; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K