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MICA polymorphisms and decreased expression of the MICA receptor NKG2D contribute to idiopathic pulmonary fibrosis susceptibility

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Abstract

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 γδ 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.

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References

  • American Thoracic Society (2000) Idiopathic pulmonary fibrosis: diagnosis and treatment. International consensus statement. American Thoracic Society (ATS) and the European Respiratory Society (ERS). Am J Respir Crit Care Med 161:646–664

    Google Scholar 

  • Arguello JR, Little AM, Bohan E, Goldman JM, Marsh SGE, Madrigal JA (1998) High resolution HLA class I typing by reference strand mediated conformation analysis (RSCA). Tissue Antigens 52:57–66

    Article  PubMed  CAS  Google Scholar 

  • Barrera L, Mendoza F, Zuñiga J, Estrada A, Zamora AC, Melendro EI, Ramírez R, Pardo A, Selman M (2008) Functional diversity of T-cell subpopulations in subacute and chronic hypersensitivity pneumonitis. Am J Respir Crit Care Med 177:44–55

    Article  PubMed  CAS  Google Scholar 

  • Boissel N, Rea D, Tieng V, Dulphy N, Brun M, Cayuela JM, Rousselot P, Tamouza R, Le Bouteiller P, Mahon FX, Steinle A, Charron D, Dombret H, Toubert A (2006) BCR/ABL oncogene directly controls MHC class I chain-related molecule A expression in chronic myelogenous leukemia. J Immunol 176:5108–5116

    PubMed  CAS  Google Scholar 

  • Borchers MT, Harris NL, Wesselkamper SC, Vitucci M, Cosman D (2006) NKG2D ligands are expressed on stressed human airway epithelial cells. Am J Physiol 291:L222–L231

    CAS  Google Scholar 

  • Disis ML, De la Rosa C, Goodell V, Kuan LY, Chang J, Kuus-Reichel K, Clay TM, Lyerly HK, Bhatia S, Ghanekar SA, Maino VC, Maecker HT (2006) Maximizing the retention of antigen specific lymphocyte function after cryopreservation. J Immunol Methods 308:13–18

    Article  PubMed  CAS  Google Scholar 

  • Eisele G, Wischhusen J, Mittelbronn M, Meyermann R, Waldhauer I, Steinle A, Weller M, Friese MA (2006) TGF-b and metalloproteinases differentially suppress NKG2D ligand surface expression on malignant glioma cells. Brain 129:2416–2425

    Article  PubMed  Google Scholar 

  • Falfán-Valencia R, Camarena A, Juárez A, Becerril C, Montaño M, Cisneros J, Mendoza F, Granados J, Pardo A, Selman M (2005) Major histocompatibility complex and alveolar epithelial apoptosis in idiopathic pulmonary fibrosis. Hum Genet 118:235–244

    Article  PubMed  Google Scholar 

  • Gao X, Single RM, Karacki P, Marti D, O’Brien SJ, Carrington M (2006) Diversity of MICA and linkage disequilibrium with HLA-B in two North American populations. Human Immunol 67:152–158

    Article  CAS  Google Scholar 

  • Groh V, Brühl A, El-Gabalawy H, Nelson JL, Spies T (2003) Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis. Proc Natl Acad Sci USA 100:9452–9457

    Article  PubMed  CAS  Google Scholar 

  • Groh V, Li YQ, Cioca D, Hunder NN, Wang W, Riddell SR, Yee C, Spies T (2005) Efficient cross-priming of tumor antigen-specific T cells by dendritic cells sensitized with diverse anti-MICA opsonized tumor cells. Proc Natl Acad Sci USA 102:6461–6466

    Article  PubMed  CAS  Google Scholar 

  • Hui J, Palmer LJ, Jamesw AL, Muskz AW, Beilby JP (2006) AluyMICB dimorphism within the class I region of the major histocompatibility complex is associated with asthma and airflow obstruction in the Busselton population. Clin Exp Allergy 36:728–734

    Article  PubMed  CAS  Google Scholar 

  • Katzenstein AL, Myers JL (1998) Idiopathic pulmonary fibrosis: clinical relevance of pathologic classification. Am J Respir Crit Care Med 157:1301–1315

    PubMed  CAS  Google Scholar 

  • Katzenstein AL, Mukhopadhyay S, Myers JL (2008) Diagnosis of usual interstitial pneumonia and distinction from other fibrosing interstitial lung diseases. Hum Pathol 39:1275–1294

    Article  PubMed  Google Scholar 

  • Khalil N, Parekh TV, O’Connor R, Antman N, Kepron W, Yehaulaeshet T, Xu YD, Gold LI (2001) Regulation of the effects of TGF-beta 1 by activation of latent TGF-beta 1 and differential expression of TGF-beta receptors (T beta R-I and T beta R-II) in idiopathic pulmonary fibrosis. Thorax 56:907–915

    Article  PubMed  CAS  Google Scholar 

  • Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, Sheppard D, Chapman HA (2006) Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci USA 103:13180–13185

    Article  PubMed  CAS  Google Scholar 

  • Kinnula VL, Fattman CL, Tan RJ, Oury TD (2005) Oxidative stress in pulmonary fibrosis: a possible role for redox modulatory therapy. Am J Respir Crit Care Med 172:417–422

    Article  PubMed  Google Scholar 

  • Komatsu-Wakui M, Itsohkikuanwaaga YK, Leelayuwat C, Kashiwase K, Tanaka S, Moriyama H, Nakajima F, Park MH, Jia GJ, Chimge N-O, Sideltseva EW, Juji T (2001) Wide distribution of the MICA-MICB null haplotype in East Asians. Tissue Antigens 57:1–8

    Article  PubMed  CAS  Google Scholar 

  • Lawson WE, Loyd JE (2006) The genetic approach in pulmonary fibrosis: can it provide clues to this complex disease? Proc Am Thorac Soc 3:345–349

    Article  PubMed  CAS  Google Scholar 

  • Lee JC, Lee KM, Kim DW, Heo DS (2004) Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol 172:7335–7340

    PubMed  CAS  Google Scholar 

  • Lü M, Xia B, Li J, Ye M, Zhang X, Tan Q (2006) MICB microsatellite polymorphism is associated with ulcerative colitis in Chinese population. Clin Immunol 120:199–204

    Article  PubMed  Google Scholar 

  • Madjd Z, Spendlove I, Moss R, Bevin S, Pinder SE, Watson NFS, Ellis I, Durrant LG (2007) Upregulation of MICA on high-grade invasive operable breast carcinoma. Cancer Immun 7:17

    PubMed  Google Scholar 

  • Muñoz-Saá I, Cambra A, Pallarés L, Espinosa G, Juan A, Pujalte F, Matamoros N, Mila J, Julia MR (2005) Allelic diversity and affinity variants of MICA are imbalanced in Spanish patients with Behcet’s disease. Scand J Immunol 64:77–82

    Article  Google Scholar 

  • Osaki T, Saito H, Yoshikawa T, Matsumoto S, Tatebe S, Tsujitani S, Ikeguchi M (2007) Decreased NKG2D expression on CD8+ T cell is involved in immune evasion in patients with gastric cancer. Clin Cancer Res 13:382–387

    Article  PubMed  CAS  Google Scholar 

  • Pardo A, Barrios R, Maldonado V, Meléndez J, Pérez J, Ruíz V, Segura L, Sznajder JI, Selman M (1998) Gelatinases A and B are upregulated in lung rats by subacute hyperoxia. Pathogenetic implications. Am J Pathol 153:833–844

    PubMed  CAS  Google Scholar 

  • Peraldi MN, Berrou J, Dulphy N, Seidowsky A, Haas P, Boissel N, Metivier F, Randoux C, Kossari N, Guérin A, Geffroy S, Delavaud G, Marin-Esteban V, Glotz D, Charron D, Toubert A (2009) Oxidative stress mediates a reduced expression of the activating receptor NKG2D in NK cells from end-stage renal disease patients. J Immunol 182:1696–1705

    PubMed  CAS  Google Scholar 

  • Pérez-Rodríguez M, Argüello JR, Fischer G, Corell A, Cox ST, Robinson J, Hossain E, McWhinnie A, Travers PJ, Marsh SGE, Madrigal JA (2002) Further polymorphism of the MICA gene. Eur J Immunogenetics 29:35–46

    Article  Google Scholar 

  • Piancatelli D, Del Beato T, Oumhani K, El Aouad R, Adorno D (2005) MICA polymorphism in a population from north Morocco, Metalsa Berbers, using sequence-based typing. Human Immunol 66:931–936

    Article  CAS  Google Scholar 

  • Poggi A, Prevosto C, Zancolli M, Canevali P, Musso A, Zocchi MR (2007) NKG2D and natural cytotoxicity receptors are involved in natural killer cell interaction with self-antigen presenting cells and stromal cells. Ann N Y Acad Sci 1109:47–57

    Article  PubMed  CAS  Google Scholar 

  • Raffaghello L, Prigione I, Airoldi I, Camoriano M, Levreri I, Gambini C, Pende D, Steinle A, Ferrone S, Pistoia V (2004) Downregulation and/or release of NKG2D ligands as immune evasion strategy of human neuroblastoma. Neoplasia 6:558–568

    Article  PubMed  CAS  Google Scholar 

  • Robinson P, Stuber D, Deryckere F, Tedbury P, Lagrange M, Orfanoudakis G (2005) Identification using phage display of peptides promoting targeting and internalization into HPV-transformed cell lines. J Mol Recognit 18:175–182

    Article  PubMed  CAS  Google Scholar 

  • Selman M, Pardo A (2006) Role of epithelial cells in idiopathic pulmonary fibrosis: from innocent targets to serial killers. Proc Am Thorac Soc 3:364–372

    Article  PubMed  CAS  Google Scholar 

  • Selman M, King TE, Pardo A (2001) Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 134:136–151

    PubMed  CAS  Google Scholar 

  • Selman M, Thannickal VJ, Pardo A, Zisman DA, Martinez FJ, Lynch JP 3rd (2004) Idiopathic pulmonary fibrosis: pathogenesis and therapeutic approaches. Drugs 64:405–430

    Article  PubMed  CAS  Google Scholar 

  • Selman M, Pardo A, Barrera L, Estrada A, Watson SR, Wilson K, Aziz N, Kaminski N, Zlotnik A (2006) Gene expression profiles distinguish idiopathic pulmonary fibrosis from hypersensitivity pneumonitis. Am J Respir Crit Care Med 173:188–198

    Article  PubMed  CAS  Google Scholar 

  • Selman M, Carrillo G, Estrada A, Mejia M, Becerril C, Cisneros J, Gaxiola M, Pérez-Padilla R, Navarro C, Richards T, Dauber J, King TE Jr, Pardo A, Kaminski N (2007) Accelerated variant of idiopathic pulmonary fibrosis: clinical behavior and gene expression pattern. PLoS ONE 2(5):e482

    Article  PubMed  Google Scholar 

  • Skov S, Terndrup PM, Andresen L, Thor SP, Woetmann A, Ødum N (2005) Cancer cells become susceptible to natural killer cell killing after exposure to histone deacetylase Inhibitors due to glycogen synthase kinase-3-dependent expression of MHC class I-related chain A and B. Cancer Res 65:11136–11145

    Article  PubMed  CAS  Google Scholar 

  • Stastny P (2006) Introduction: MICA/MICB in innate immunity, adaptive immunity, autoimmunity, cancer, and in the immune response to transplants. Hum Immunol 67:141–144

    Article  PubMed  Google Scholar 

  • Steinle A, Li P, Morris DL, Groh V, Lanier LL, Strong RK, Spies T (2001) Interactions of human NKG2D with its ligands MICA, MICB, and homologs of the mouse RAE-1 protein family. Immunogenetics 53:279–287

    Article  PubMed  CAS  Google Scholar 

  • Suemizu H, Radosavljevic M, Kimura M, Sadahiro S, Yoshimura S, Bahram S, Inoko H (2002) A basolateral sorting motif in the MICA cytoplasmic tail. Proc Natl Acad Sci USA 99:2971–2976

    Article  PubMed  CAS  Google Scholar 

  • Tamaki S, Kawakami M, Yamanaka Y, Shimomura H, Imai Y, Ishida JI, Yamamoto K, Ishitani A, Hatake K, Kirita T (2008) Relationship between soluble MICA and the MICA A5.1 homozygous genotype in patients with oral squamous cell carcinoma. Clin Immunol 130:331–337

    Article  PubMed  Google Scholar 

  • Thannickal VJ, Horowitz JC (2006) Evolving concepts of apoptosis in idiopathic pulmonary fibrosis. Proc Am Thorac Soc 3:350–356

    Article  PubMed  CAS  Google Scholar 

  • Törn C, Gupta M, Zake LN, Sanjeevi CB, Landin-Olsson M (2003) Heterozygosity for MICA5.0/MICA5.1 and HLA-DR3-DQ2/DR4-DQ8 are Independent genetic risk factors for latent autoimmune diabetes in adults. Human Immunol 64:902–909

    Article  Google Scholar 

  • Waldhauer I, Steinle A (2006) Proteolytic release of soluble UL16-binding protein 2 from tumor cells. Cancer Res 66:2520–2526

    Article  PubMed  CAS  Google Scholar 

  • Waldhauer I, Goehlsdorf D, Gieseke F, Weinschenk T, Wittenbrink M, Ludwig A, Stevanovic S, Rammensee HG, Steinle A (2008) Tumor-associated MICA is shed by ADAM proteases. Cancer Res 68:6368–6376

    Article  PubMed  CAS  Google Scholar 

  • Willis BC, Liebler JM, Luby-Phelps K, Nicholson AG, Crandall ED, du Bois RM, Borok Z (2005) Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. Am J Pathol 166:1321–1332

    PubMed  CAS  Google Scholar 

  • Wu J, Groh V, Spies T (2002) T Cell antigen receptor engagement and specificity in the recognition of stress-inducible MHC class I-related chains by human epithelial γδ T cells. J Immunol 169:1236–1240

    PubMed  CAS  Google Scholar 

  • Xu X, Rao G, Gaffud MJ, Ding HG, Maki G, Klingemann H-G, Groh V, Spies T, Sp Caillat-Zucman, Gattuso P, Plate J, Prinz RA (2006) Clinicopathological significance of major histocompatibility complex class I-related chain A and B expression in thyroid cancer. J Clin Endocrinol Metab 91:2704–2712

    Article  PubMed  CAS  Google Scholar 

  • Zhang T, Barber A, Sentman CL (2006) Generation of antitumor responses by genetic modification of primary human T cells with a chimeric NKG2D receptor. Cancer Res 66:5927–5933

    Article  PubMed  CAS  Google Scholar 

  • Zhang S, Hüe S, Sène D, Penfornis A, Bresson-Hadni S, Kantelip B, Caillat-Zucman S, Vuitton DA (2008) Expression of major histocompatibility complex class I chain-related molecule A, NKG2D, and transforming growth factor-beta in the liver of humans with alveolar echinococcosis: new actors in the tolerance to parasites? J Infect Dis 197:1341–1349

    Article  PubMed  Google Scholar 

  • Zou Y, Mirbaha F, Stastny P (2006) Contact inhibition causes strong downregulation of expression of MICA in human fibroblasts and decreased NK Cell killing. Human Immunol 67:183–187

    Article  CAS  Google Scholar 

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Acknowledgments

This study was supported by Universidad Nacional Autónoma de México, Grant SDI.PTID.05.6.

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Authors and Affiliations

  1. Instituto Nacional de Enfermedades Respiratorias, “Ismael Cosío Villegas”, Tlalpan 4502, CP 14080, Mexico DF, Mexico

    Arnoldo Aquino-Galvez, Ángel Camarena, Ramces Falfan-Valencia, Víctor Ruiz, Martha Montaño, Lourdes Barrera, Isabel Sada-Ovalle & Moisés Selman

  2. Unidad de Investigación Médica en Inmunología, CMN S-XXI Instituto Mexicano del Seguro Social, Mexico DF, Mexico

    Martha Pérez-Rodríguez

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

    Remedios Ramírez & Annie Pardo

  4. Instituto Nacional de Ciencias Médicas y Nutrición “Salvador Zubirán”, Mexico DF, Mexico

    Julio Granados

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  1. Arnoldo Aquino-Galvez
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  2. Martha Pérez-Rodríguez
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  12. Moisés Selman
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Correspondence to Moisés Selman.

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This work was submitted in partial fulfillment of the requirements to obtain the PhD degree for AAG at Biological Sciences, UNAM.

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Aquino-Galvez, A., Pérez-Rodríguez, M., Camarena, Á. et al. MICA polymorphisms and decreased expression of the MICA receptor NKG2D contribute to idiopathic pulmonary fibrosis susceptibility. Hum Genet 125, 639–648 (2009). https://doi.org/10.1007/s00439-009-0666-1

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