Expression of Selected Integrins and Selectins in Bullous Pemphigoid

Abstract

Blister development in bullous pemphigoid (BP) results from destruction of hemidesmosomes and basement membrane components within the dermoepidermal junction by autoantibodies. Adhesion molecules can take part in pathogenesis of this disease. The aim of the study was to determine the localization and expression of L- and E-selectins and β1, β3, and β4 integrins by immunohistochemistry in skin lesions of 21 patients with BP, compared with 10 healthy subjects. Expression of L and E selectins and β1, β3 integrins was detected mainly in basal keratinocytes and in inflammatory infiltrates in the dermis, expression of β4 integrin was irregular and was detected mainly in dermal part of the blister, while in the control group only weak and single expression of the examined molecules was detected in basal keratinocytes and endothelium cells. The obtained results reveal the important role of selected selectins and integrins in development of skin lesions in BP.

References

1. J. R. Stanley, “Cell adhesion molecules as targets of autoantibodies in pemphigus and pemphigoid, bullous diseases due to defective epidermal cell adhesion,” Advances in Immunology, vol. 53, pp. 291–325, 1993. View at: Google Scholar
2. E. Schmidt, K. Obe, E.-B. Bröcker;, and D. Zillikens, “Serum levels of autoantibodies to BP180 correlate with disease activity in patients with bullous pemphigoid,” Archives of Dermatology, vol. 136, no. 2, pp. 174–178, 2000. View at: Publisher Site | Google Scholar
3. R. E. Jordon, E. H. Beutner, E. Witebsky, G. Blumental, W. L. Hale, and W. F. Lever, “Basement zone antibodies in bullous pemphigoid,” Journal of the American Medical Association, vol. 200, no. 9, pp. 751–756, 1967. View at: Publisher Site | Google Scholar
4. E. Schmidt, S. Reimer, N. Kruse et al., “Autoantibodies to BP180 associated with bullous pemphigoid release interleukin-6 and interleukin-8 from cultured human keratinocytes,” Journal of Investigative Dermatology, vol. 115, no. 5, pp. 842–848, 2000. View at: Publisher Site | Google Scholar
5. S. A. Grando, B. T. Glukhenky, G. N. Drannik, E. V. Epshtein, A. P. Kostromin, and T. A. Korostash, “Mediators of inflammation in blister fluids from patients with pemphigus vulgaris and bullous pemphigoid,” Archives of Dermatology, vol. 125, no. 7, pp. 925–930, 1989. View at: Publisher Site | Google Scholar
6. M. Ståhle-Bäckdahl, M. Inoue, G. J. Giudice, and W. C. Parks, “92-kD gelatinase is produced by eosinophils at the site of blister formation in bullous pemphigoid and cleaves the extracellular domain of recombinant 180-kD bullous pemphigoid autoantigen,” Journal of Clinical Investigation, vol. 93, no. 5, pp. 2022–2030, 1994. View at: Google Scholar
7. A. J. Freemont, “Demystified ... adhesion molecules,” Journal of Clinical Pathology—Molecular Pathology, vol. 51, no. 4, pp. 175–184, 1998. View at: Google Scholar
8. M. Graeber, B. S. Baker, J. J. Garioch, H. Valdimarsson, J. N. Leonard, and L. Fry, “The role of cytokines in the generation of skin lesions in dermatitis herpetiformis,” British Journal of Dermatology, vol. 129, no. 5, pp. 530–532, 1993. View at: Publisher Site | Google Scholar
9. Z. Liu, M. Zhao, N. Li, L. A. Diaz, and T. N. Mayadas, “Differential roles for ${\beta }_2$ integrins in experimental autoimmune bullous pemphigoid,” Blood, vol. 107, no. 3, pp. 1063–1069, 2006. View at: Publisher Site | Google Scholar
10. U. H. von Andrian and B. Engelhardt, “${\alpha }_4$ integrins as therapeutic targets in autoimmune disease,” New England Journal of Medicine, vol. 348, no. 1, pp. 68–72, 2003. View at: Publisher Site | Google Scholar
11. A. Moreno, C. Lucena, A. López, J. J. Garrido, L. L. de Pérez, and D. Llanes, “Immunohistochemical analysis of ${\beta }_3$ integrin (CD61): expression in pig tissues and human tumors,” Histology and Histopathology, vol. 17, no. 2, pp. 347–352, 2002. View at: Google Scholar
12. A. E. Berman, N. I. Kozlova, and G. E. Morozevich, “Integrins: structure and signaling,” Biochemistry (Moscow), vol. 68, no. 12, pp. 1284–1299, 2003. View at: Publisher Site | Google Scholar
13. J.-P. Xiong, T. Stehle, S. L. Goodman, and M. A. Arnaout, “New insights into the structural basis of integrin activation,” Blood, vol. 102, no. 4, pp. 1155–1159, 2003. View at: Publisher Site | Google Scholar
14. R. O. Hynes, “Integrins: versatility, modulation, and signaling in cell adhesion,” Cell, vol. 69, no. 1, pp. 11–25, 1992. View at: Publisher Site | Google Scholar
15. M. H. Ginsberg, X. Du, and E. F. Plow, “Inside-out integrin signalling,” Current Opinion in Cell Biology, vol. 4, no. 5, pp. 766–771, 1992. View at: Publisher Site | Google Scholar
16. T. E. O'Toole, Y. Katagiri, R. J. Faull et al., “Integrin cytoplasmic domains mediate inside-out signal transduction,” Journal of Cell Biology, vol. 124, no. 6, pp. 1047–1059, 1994. View at: Publisher Site | Google Scholar
17. R. O. Hynes, “Integrins: bidirectional, allosteric signaling machines,” Cell, vol. 110, no. 6, pp. 673–687, 2002. View at: Publisher Site | Google Scholar
18. T. A. Springer, “Adhesion receptors of the immune system,” Nature, vol. 346, no. 6283, pp. 425–434, 1990. View at: Publisher Site | Google Scholar
19. D. Bouvard, C. Brakebusch, E. Gustafsson et al., “Functional consequences of integrin gene mutations in mice,” Circulation Research, vol. 89, no. 3, pp. 211–223, 2001. View at: Google Scholar
20. M. A. Stepp, S. Spurr-Michaud, A. Tisdale, J. Elwell, and I. K. Gipson, “${\alpha }_6{\beta }_4$ integrin heterodimer is a component of hemidesmosomes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 22, pp. 8970–8974, 1990. View at: Publisher Site | Google Scholar
21. J. Koster, D. Geerts, B. Favre, L. Borradori, and A. Sonnenberg, “Analysis of the interactions between BP180, BP230, plectin and the integrin ${\alpha }_6{\beta }_4$ important for hemidesmosome assembly,” Journal of Cell Science, vol. 116, no. 2, pp. 387–399, 2003. View at: Publisher Site | Google Scholar
22. X.-Y. Liu, S. Timmons, Y.-Z. Lin, and J. Hawiger, “Identification of a functionally important sequence in the cytoplasmic tail of integrin ${\beta }_3$ by using cell-permeable peptide analogs,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 21, pp. 11819–11824, 1996. View at: Publisher Site | Google Scholar
23. R. A. J. Eady, “The hemidesmosome: a target in auto-immune bullous disease,” Dermatology, vol. 189, supplement 1, pp. 38–41, 1994. View at: Google Scholar
24. L. Borradori, P. J. Koch, C. M. Niessen, S. Erkeland, M. R. Van Leusden, and A. Sonnenberg, “The localization of bullous pemphigoid antigen 180 (BP180) in hemidesmosomes is mediated by its cytoplasmic domain and seems to be regulated by the ${\beta }_4$ integrin subunit,” Journal of Cell Biology, vol. 136, no. 6, pp. 1333–1347, 1997. View at: Publisher Site | Google Scholar
25. S. B. Hopkinson, K. Findlay, G. W. deHart, and J. C. R. Jones, “Interaction of BP180 (type XVII collagen) and ${\alpha }_6$ integrin is necessary for stabilization of hemidesmosome structure,” Journal of Investigative Dermatology, vol. 111, no. 6, pp. 1015–1022, 1998. View at: Publisher Site | Google Scholar
26. S. Kumari, K. C. Bhol, R. K. Simmons et al., “Identification of ocular cicatricial pemphigoid antibody binding site(s) in human ${ß}_4$ integrin,” Investigative Ophthalmology and Visual Science, vol. 42, no. 2, pp. 379–385, 2001. View at: Google Scholar
27. M. Leverkus, K. Bhol, Y. Hirako et al., “Cicatricial pemphigoid with circulating autoantibodies to ${ß}_4$ integrin, bullous pemphigoid 180 and bullous pemphigoid 230,” British Journal of Dermatology, vol. 145, no. 6, pp. 998–1004, 2001. View at: Publisher Site | Google Scholar
28. R. Y. Chan, K. Bhol, N. Tesavibul et al., “The role of antibody to human ${ß}_4$ integrin in conjunctival basement membrane separation: possible in vitro model for ocular cicatricial pemphigoid,” Investigative Ophthalmology and Visual Science, vol. 40, no. 10, pp. 2283–2290, 1999. View at: Google Scholar
29. S. Tyagi, K. Bhol, K. Natarajan, C. Livir-Rallatos, C. S. Foster, and A. R. Ahmed, “Ocular cicatricial pemphigoid antigen: partial sequence and biochemical characterization,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 25, pp. 14714–14719, 1996. View at: Publisher Site | Google Scholar
30. K. C. Bhol, L. Goss, S. Kumari, J. E. Colon, and A. R. Ahmed, “Autoantibodies to human ${\alpha }_6$ integrin in patients with oral pemphigoid,” Journal of Dental Research, vol. 80, no. 8, pp. 1711–1715, 2001. View at: Google Scholar
31. K. C. Bhol, M. J. Dans, R. K. Simmons, C. S. Foster, F. G. Giancotti, and A. R. Ahmed, “The autoantibodies to ${\alpha }_6{\beta }_4$ integrin of patients affected by ocular cicatricial pemphigoid recognize predominantly epitopes within the large cytoplasmic domain of human ${\beta }_4$,” Journal of Immunology, vol. 165, no. 5, pp. 2824–2829, 2000. View at: Google Scholar
32. K. A. Rashid, J. N. H. Stern, and A. R. Ahmed, “Identification of an epitope within human integrin ${\alpha }_6$ subunit for the binding of autoantibody and its role in basement membrane separation in oral pemphigoid,” Journal of Immunology, vol. 176, no. 3, pp. 1968–1977, 2006. View at: Google Scholar
33. M. A. Kurpakus, V. Quaranta, and J. C. R. Jones, “Surface relocation of ${\alpha }_6{\beta }_4$ integrins and assembly of hemidesmosomes in an in vitro model of wound healing,” Journal of Cell Biology, vol. 115, no. 6, pp. 1737–1750, 1991. View at: Publisher Site | Google Scholar
34. L. D'Auria, P. Cordiali Fei, M. Pietravalle et al., “The serum levels of sE-selectin are increased in patients with bullous pemphigoid or pemphigus vulgaris. Correlation with the number of skin lesions and recovery after corsticosteroid therapy,” British Journal of Dermatology, vol. 137, no. 1, pp. 59–64, 1997. View at: Publisher Site | Google Scholar
35. W. E. Parish, “Inflammation,” in Rook, Wilkinson, Ebling Textbook of Dermatology, R. H. Champion, J. L. Burton, D. A. Burner, and S. M. Breathnach, Eds., pp. 229–276, Blackwell Science, Oxford, UK, 6th edition, 1998. View at: Google Scholar
36. S. Ghosh, E. Goldin, F. H. Gordon et al., “Natalizumab for active Crohn's disease,” New England Journal of Medicine, vol. 348, no. 1, pp. 24–32, 2003. View at: Publisher Site | Google Scholar

Copyright

Copyright © 2007 Agnieszka Żebrowska et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.