Estamos trabajando para incorporar este artículo al repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor


The MICA/B genes (MHC class I chain related genes A and B) encode for non conventional class I HLA molecules which have no role in antigen presentation. MICA/B are up-regulated by different stress conditions such as heat-shock, oxidative stress, neoplasic transformation and viral infection. Particularly, MICA/B are expressed in enterocytes where they can mediate enterocyte apoptosis when recognised by the activating NKG2D receptor present on intraepithelial lymphocytes. This mechanism was suggested to play a major pathogenic role in active celiac disease (CD). Due to the importance of MICA/B in CD pathogenesis we studied their expression in duodenal tissue from CD patients. By immunofluorescence confocal microscopy and flow cytometry we established that MICA/B was mainly intracellularly located in enterocytes. In addition, we identified MICA/B+ T cells in both the intraepithelial and lamina propria compartments. We also found MICA/B+ B cells, plasma cells and some macrophages in the lamina propria. The pattern of MICA/B staining in mucosal tissue in severe enteropathy was similar to that found in in vitro models of cellular stress. In such models, MICA/B were located in stress granules that are associated to the oxidative and ER stress response observed in active CD enteropathy. Our results suggest that expression of MICA/B in the intestinal mucosa of CD patients is linked to disregulation of mucosa homeostasis in which the stress response plays an active role. © 2013 Allegretti et al.


Documento: Artículo
Título:Broad MICA/B Expression in the Small Bowel Mucosa: A Link between Cellular Stress and Celiac Disease
Autor:Allegretti, Y.L.; Bondar, C.; Guzman, L.; Cueto Rua, E.; Chopita, N.; Fuertes, M.; Zwirner, N.W.; Chirdo, F.G.
Filiación:Laboratorio de Investigación en el Sistema Inmune - LISIN, Departamento de Ciencias Biológicas, Universidad Nacional de La Plata, La Plata, Argentina
Servicio de Gastroenterología, Hospital de Niños Sor María Ludovica, La Plata, Argentina
Servicio de Gastroenterología, Hospital San Martin La Plata, La Plata, Argentina
Laboratorio de Fisiopatología de la Inmunidad Innata, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
Departamento de Química Biológica, Universidad de Buenos Aires, Buenos Aires, Argentina
Departamento de Microbiología, Parasitología e Inmunología, Universidad de Buenos Aires, Buenos Aires, Argentina
Palabras clave:CD20 antigen; CD3 antigen; CD68 antigen; CD7 antigen; glycoprotein p 15095; major histocompatibility antigen class 1; major histocompatibility antigen class 2; syndecan 1; article; B lymphocyte; celiac disease; cell stress; cellular distribution; child; clinical article; confocal microscopy; controlled study; disease severity; endoplasmic reticulum stress; flow cytometry; gene; gene expression regulation; human; human cell; human tissue; immune dysregulation; immunofluorescence test; immunopathogenesis; intestine biopsy; lamina propria; macrophage; MICA gene; MICAB gene; oxidative stress; preschool child; protein localization; small intestine mucosa; B-Lymphocytes; Celiac Disease; Child, Preschool; Duodenum; Enterocytes; Female; Gene Expression; Histocompatibility Antigens Class I; Humans; Intestinal Mucosa; Macrophages; Male; Plasma Cells; Severity of Illness Index; Stress, Physiological; T-Lymphocytes
Título revista:PLoS ONE
Título revista abreviado:PLoS ONE
CAS:syndecan 1, 128559-86-4


  • Stastny, P., MICA/MICB in innate immunity, adaptive immunity, autoimmunity, cancer, and in the immune response to transplants (2006) Hum Immunol, 67 (3), pp. 141-144
  • Groh, V., Bahram, S., Bauer, S., Herman, A., Beauchamp, M., Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium (1996) Proc Natl Acad Sci, 93, pp. 12445-12450
  • Groh, V., Steinle, A., Bauer, S., Spies, T., Recognition of stress induced MHC molecules by intestinal epithelial gammadelta T cells (1998) Science, 279, pp. 1737-1740
  • Venkataraman, G.M., Suciu, D., Groh, V., Boss, J.M., Spies, T., Promoter region architecture and transcriptional regulation of the genes for the MHC class I-related chain A and B ligands of NKG2D (2007) J Immunol, 178, pp. 961-969
  • Groh, V., Rhinehart, R., Randolph-Habecker, J., Topp, M.S., Riddell, S.R., Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells (2001) Nat Immunol, 2, pp. 255-260
  • Eagle, R.A., Trowsdale, J., Promiscuity and the single receptor: NKG2D (2007) Nat Rev Immunol, 7, pp. 737-744
  • Roberts, A.I., Lee, L., Schwarz, E., Groh, V., Spies, T., NKG2D receptors induced by IL-15 co-stimulate CD28-negative effector CTL in the tissue microenvironment (2001) J Immunol, 167, pp. 5527-5530
  • Ebert, E.C., IL-15 converts human intestinal intraepithelial lymphocytes to CD94 producers of IFN-gamma and IL-10, the latter promoting Fas ligand-mediated cytotoxicity (2005) Immunol, 115 (1), pp. 118-126
  • Gleimer, M., Parham, P., Stress Management: MHC Class I Review and Class I-like Molecules as Reporters of Cellular Stress (2003) Immunity, 19, pp. 469-477
  • Hue, S., Mention, J.J., Monteiro, R.C., Zhang, S.L., Cellier, C., A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease (2004) Immunity, 21, pp. 367-377
  • Meresse, B., Chen, Z., Ciszewski, C., Tretiakova, M., Bhagat, G., Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease (2004) Immunity, 21 (3), pp. 357-366
  • Abadie, V., Sollid, L.M., Barreiro, L.B., Jabri, B., Integration of genetic and immunological insights into a model of celiac diseasepathogenesis (2011) Annu Rev Immunol, 9, pp. 493-525
  • Maiuri, L., Ciacci, C., Ricciardelli, I., Vacca, L., Raia, V., Association between innate response to gliadin and activation of pathogenic T cells in celiac disease (2003) Lancet, 362, pp. 30-37
  • Luciani, A., Villella, V.R., Vasaturo, A., Giardino, I., Pettoello-Mantovani, M., Lysosomal accumulation of gliadin p31-43 peptide induces oxidative stress and tissue transglutaminase-mediated PPARgamma downregulation in intestinal epithelial cells and celiac mucosa (2010) Gut, 59 (3), pp. 311-319
  • Maiuri, L., Ciacci, C., Auricchio, S., Brown, V., Quaratino, S., Interleukin 15 mediates epithelial changes in celiac disease (2000) Gastroenterology, 119, pp. 996-1006
  • Mention, J.J., Ben Ahmed, M., Begue, B., Barbe, U., Verkarre, V., Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease (2003) Gastroenterology, 125, pp. 730-745
  • Bernardo, D., Garrote, J.A., Allegretti, Y., León, A., Gómez, E., Higher constitutive IL15Ra expression and lower IL-15 response threshold in Coeliac Disease patients (2008) Clin Exp Immunol, 154 (1), pp. 64-73
  • Martin-Pagola, A., Ortiz, L., Perez-Nanclares, G., Vitoria, J.C., Castano, L., Analysis of the expression of MICA in small intestinal mucosa of patients with celiac disease (2003) J Clin Immunol, 23 (6), pp. 498-503
  • Martín-Pagola, A., Pérez-Nanclares, G., Ortiz, L., Vitoria, J.C., Hualde, I., MICA response to gliadin in intestinal mucosa from celiac patients (2004) Immunogenetics, 56 (8), pp. 549-554
  • Molinero, L.L., Fuertes, M.B., Girart, M.V., Fainboim, L., Rabinovich, G.A., NF-kappa B regulates expression of the MHC class I-related chain A gene in activated T lymphocytes (2004) J Immunol, 173 (9), pp. 5583-5590
  • Gülow, K., Bienert, D., Haas, I.G., BiP is feed-back regulated by control of protein translation efficiency (2002) J Cell Sci, 115 (Pt 11), pp. 2443-2452
  • Kedersha, N.L., Gupta, M., Li, W., Miller, I., Anderson, P., RNA-binding proteins TIA-1 and TIAR link the phosphorylation of eIF-2 alpha to the assembly of mammalian stress granules (1999) J Cell Biol, 147 (7), pp. 1431-1442
  • Thomas, M.G., Martinez Tosar, L.J., Desbats, M.A., Leishman, C.C., Boccaccio, G.L., Mammalian Staufen 1 is recruited to stress granules and impairs their assembly (2009) J Cell Sci, 122 (Pt 4), pp. 563-573
  • Ostberg, J.R., Kaplan, K.C., Repasky, E.A., Induction of stress proteins in a panel of mouse tissues by fever-range whole body hyperthermia (2002) Int J Hyperthermia, 18 (6), pp. 552-562
  • Moss, S.F., Attia, L., Scholes, J.V., Walters, J.R., Holt, P.R., Increased small intestinal apoptosis in celiac disease (1996) Gut, 39, pp. 811-817
  • Yang, P.C., He, S.H., Zheng, P.Y., Investigation into the signal transduction pathway via which heat stress impairs intestinal epithelial barrier function (2007) J Gastroenterol Hepatol, 22 (11), pp. 1823-1831
  • Ferretti, G., Bacchetti, T., Masciangelo, S., Saturni, L., Celiac disease, inflammation and oxidative damage: a nutrigenetic approach (2012) Nutrients, 4 (4), pp. 243-257
  • Circu, M.L., Aw, T.Y., Intestinal redox biology and oxidative stress (2012) Semin Cell Dev Biol, 23 (7), pp. 729-737
  • Adolph, T.E., Niederreiter, L., Blumberg, R.S., Kaser, A., Endoplasmic reticulum stress and inflammation (2012) Dig Dis, 30 (4), pp. 341-346
  • Stojiljković, V., Todorović, A., Pejić, S., Kasapović, J., Saicić, Z.S., Antioxidant status and lipid peroxidation in small intestinal mucosa of children with celiac disease (2009) Clin Biochem, 42 (13-14), pp. 1431-1437
  • Daniels, I., Cavill, D., Murray, I.A., Long, R.G., Elevated expression of iNOS mRNA and protein in celiac disease (2005) Clin Chim Acta, 356 (1-2), pp. 134-142
  • Caputo, I., Secondo, A., Lepretti, M., Paolella, G., Auricchio, S., Gliadin peptides induce tissue transglutaminase activation and ER-stress through Ca2+ Mobilization in Caco-2 cells (2012) PLoS One, 7 (9), pp. e45209
  • Gilks, N., Kedersha, N., Ayodele, M., Shen, L., Stoecklin, G., Stress granule assembly is mediated by prion-like aggregation of TIA-1. 2004 (2004) Mol Biol Cell, 15 (12), pp. 5383-5398
  • Thomas, K.E., Sapone, A., Fasano, A., Vogel, S.N., Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: role of the innate immune response in Celiac disease (2006) J Immunol, 176 (4), pp. 2512-2521
  • Barone, M.V., Zanzi, D., Maglio, M., Nanayakkara, M., Santagata, S., Gliadin-mediated proliferation and innate immune activation in celiac disease are due to alterations in vesicular trafficking (2011) PLoS One, 6 (2), pp. e17039
  • Rivabene, R., Mancini, E., De Vincenzi, M., In vitro cytotoxic effect of wheat gliadin-derived peptides on the Caco-2 intestinal cell line is associated with intracellular oxidative imbalance: implications for celiac disease (1999) Biochim Biophys Acta, 1453 (1), pp. 152-160
  • Iltanen, S., Rantala, I., Laippala, P., Holm, K., Partanen, J., Expression of HSP-65 in jejunal epithelial cells in patients clinically suspected of celiac disease (1999) Autoimmunity, 31 (2), pp. 125-132
  • Molinero, L.L., Fuertes, M.B., Rabinovich, G.A., Fainboim, L., Zwirner, N.W., Activation-induced expression of MICA on T lymphocytes involves engagement of CD3 and CD28 (2002) J Leukoc Biol, 71 (5), pp. 791-797
  • Molinero, L.L., Fuertes, M.B., Fainboim, L., Rabinovich, G.A., Zwirner, N.W., Up-regulated expression of MICA on activated T lymphocytes involves Lck and Fyn kinases and signaling through MEK1/ERK, p38 MAP kinase, and calcineurin (2003) J Leukoc Biol, 73 (6), pp. 815-822
  • Cerboni, C., Zingoni, A., Cippitelli, M., Piccoli, M., Frati, L., Antigen-activated human T lymphocytes express cell-surface NKG2D ligands via an ATM/ATR-dependent mechanism and become susceptible to autologous NK- cell lysis (2007) Blood, 110 (2), pp. 606-615
  • Matusali, G., Tchidjou, H.K., Pontrelli, G., Bernardi, S., D'Ettorre, G., Soluble ligands for the NKG2D receptor are released during HIV-1 infection and impair NKG2D expression and cytotoxicity of NK cells (2013) FASEB J, 27 (6), pp. 2440-2450
  • Nielsen, N., Ødum, N., Ursø, B., Lanier, L.L., Spee, P., Cytotoxicity of CD56(bright) NK cells towards autologous activated CD4+ T cells is mediated through NKG2D, LFA-1 and TRAIL and dampened via CD94/NKG2A (2012) PLoS One, 7 (2), pp. e31959
  • Meresse, B., Malamut, G., Cerf-Bensussan, N., Celiac disease: an immunological jigsaw (2012) Immunity, 36 (6), pp. 907-919


---------- APA ----------
Allegretti, Y.L., Bondar, C., Guzman, L., Cueto Rua, E., Chopita, N., Fuertes, M., Zwirner, N.W.,..., Chirdo, F.G. (2013) . Broad MICA/B Expression in the Small Bowel Mucosa: A Link between Cellular Stress and Celiac Disease. PLoS ONE, 8(9).
---------- CHICAGO ----------
Allegretti, Y.L., Bondar, C., Guzman, L., Cueto Rua, E., Chopita, N., Fuertes, M., et al. "Broad MICA/B Expression in the Small Bowel Mucosa: A Link between Cellular Stress and Celiac Disease" . PLoS ONE 8, no. 9 (2013).
---------- MLA ----------
Allegretti, Y.L., Bondar, C., Guzman, L., Cueto Rua, E., Chopita, N., Fuertes, M., et al. "Broad MICA/B Expression in the Small Bowel Mucosa: A Link between Cellular Stress and Celiac Disease" . PLoS ONE, vol. 8, no. 9, 2013.
---------- VANCOUVER ----------
Allegretti, Y.L., Bondar, C., Guzman, L., Cueto Rua, E., Chopita, N., Fuertes, M., et al. Broad MICA/B Expression in the Small Bowel Mucosa: A Link between Cellular Stress and Celiac Disease. PLoS ONE. 2013;8(9).